PHENYL-THIOPHENE TYPE VITAMIN D RECEPTOR MODULATORS

Description

BACKGROUND OF THE INVENTION

[0001] Vitamin D₃ Receptor (VDR) is a ligand dependent transcription factor that belongs to the superfamily of nuclear hormone receptors. The VDR protein is 427 amino acids, with a molecular weight of ∼50 kDa. The VDR ligand, 1α,25-dihydroxyvitamin D3 (the hormonally active form of Vitamin D) has its action mediated by its interaction with the nuclear receptor known as Vitamin D receptor ("VDR"). The VDR ligand, 1α,25-dihydroxyvitamin D3 (1α,25(OH)₂D₃) acts upon a wide variety of tissues and cells both related to and unrelated to calcium and phosphate homeostasis.

[0002] The activity of 1α,25-dihydroxyvitamin D3 (1α,25(OH)₂D₃)in various systems suggests wide clinical applications. However, use of conventional VDR ligands is hampered by their associated toxicity, namely hypercalcemia (elevated serum catcium). Currently, 1α,25(OH)₂D₃, marketed as Rocaltrol® pharmaceutical agent (product of Hoffmann-La Roche), is administered to kidney failure patients undergoing chronic kidney dialysis to treat hypocalcemia and the resultant metabolic bone disease. Other therapeutic agents, such as Calcipotriol® (synthetic analog of 1α,25(OH)₂D₃ ) show increased separation of binding affinity on VDR from hypercalcemic activity.

[0003] Recently, chemical modifications of 1α,25(OH)₂D₃ have yielded analogs with attenuated calcium mobilization effects (R. Bouillon et. al., Endocrine Rev. 1995, 16, 200-257). One such analog, Dovonex ® pharmaceutical agent (product of Bristol-Meyers Squibb Co.), is currently used in Europe and the United States as a topical treatment for mild to moderate psoriasis (K. Kragballe et. al., Br. J. Dermatol. 1988, 119, 223-230).

[0004] Other vitamin D₃ mimics have been described in the publication, Vitamin D Analogs: Mechanism of Action of Therapeutic Applications, by Nagpal, S.; Lu, J.; Boehm, M. F., Curr. Med. Chem. 2001, 8, 1661-1679.

[0005] Although some degree of separation between the beneficial action and calcium raising (calcemic) effects has been achieved with these VDR ligands, to date the separation has been insufficient to allow for oral administration to treat conditions such as osteoporosis, cancers, leukemias, and severe psoriasis.

[0006] One example of a major class of disorder that could benefit from VDR mediated biological efficacy in the absence of hypercalcemia is osteoporosis. Osteoporosis is a systemic disorder characterized by decreased bone mass and microarchitectural deterioration of bone tissue leading to bone fragility and increased susceptibility to fractures of the hip, spine, and wrist (World Health Organization WHO 1994). Osteoporosis affects an estimated 75 million people in the United States, Europe, and Japan.

[0007] Within the past few years, several antiresorptive therapies have been introduced. These include bisphosphonates, hormone replacement therapy (HRT), a selective estrogen receptor modulator (SERM), and calcitonins. These treatments reduce bone resorption, bone formation, and increase bone density. However, none of these treatments increase true bone volume nor can they restore lost bone architecture.

[0008] Synthetic vitamin D receptor (VDR) ligands with reduced calcemic potential have been synthesized. For example, a class of bis-phenyl compounds stated to mimic 1α, 25-dihydroxyvitamin D₃ is described in US Patent No. 6,218,430 and the article; "Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1α, 25-Dihydroxyvitarnin D3" by Marcus F. Boehm, et al., Chemistry & Biology 1999, Vol 6, No. 5, pgs. 265-275.

[0009] There remains a need for improved treatments using alternative or improved pharmaceutical agents that mimic 1α, 25-dibydroxyvitamin D₃ to stimulate bone formation, restore bone quality, and treat other diseases without the attendant disadvantage of hypercalcemia.

SUMMARY OF THE INVENTION

[0010] The compounds described herein have been found effective as Vitamin D Receptor (VDR) modulators.

[0011] The inventors have discovered that compounds described herein display the desirable cell differentiation and antiproliferative effects of 1,25(OH)₂D₃ with reduced calcium mobilization (calcemic) effects.

[0012] In another aspect, the present invention is directed towards pharmaceutical compositions containing pharmaceutically effective amounts of compounds of formulae I or a pharmaceutically acceptable salt or prodrug thereof, either singly or in combination, together with pharmaceutically acceptable carriers and/or auxiliary agents.

[0013] Another aspect is the compounds of the present invention for use in the prevention and treatment of abscess, acne, adhesion, actinic keratosis, alopecia, Alzheimer's disease, autoimmune induced diabetes, bone fracture healing, breast cancer, Crohn's disease, colon cancer, Type I diabetes, host-graft rejection, hypercalcemia , Type II diabetes, leukemia, multiple sclerosis, insufficient sebum secretion, osteomalacia, osteoporosis, insufficient dermal firmness, insufficient dermal hydration, myelodysplastic syndrome, psoriatic arthritis, prostate cancer, psoriasis, renal osteodystrophy, rheumatoid arthritis, scleroderma, seborrheic dermatitis, skin cancer, systemic lupus erythematosis, ulcerative colitis and wrinkles.

[0014] The symbol, "*" in a structural formula identifies a chiral center.

[0015] The univalent symbol "-O" in any structural formula is a hydroxyl group (-OH).

[0016] The term "pharmaceutically acceptable salt" includes salts of the compounds of the present invention derived from the combination of the compound and an organic or inorganic acid or base. In practice, acidic members of the compounds of the present invention would be combined with a base or bases, basic members of the compounds of the present invention would be combined with an acid or acids, and members of the compounds of the present invention with both acid and base functionalities would be combined with one or more acids, bases or any combination thereof. Both the neutral and salt forms fall within the scope of the present invention. Examples of cationic salts are sodium, aluminum, zinc, potassium, calcium, magnesium and ammonium.

[0017] The word "abscess" is a complication often associated with surgery, trama, or diseases that predispose the host to abscess formation from encapsulated bacteria lymphocytes, macrophages, and etc.

[0018] The word "adhesion" refers to the abnormal union of surfaces normally separate by the formulation of new fibrous tissue resulting from an inflammatory

[0019] Some of the structural formulae used herein omit depiction of hydrogen atoms. For example, the formula:

is understood to be the equivalent of the formula:

[0020] Compounds useful in practicing the therapeutic methods of the invention as shown in the structural formulae X1 to X188, as follows:

[0021] Particularly preferred chemical species of the invention are represented by structural formulae P101 to P106 and P200 to P206 or a pharmaceutically acceptable salt thereof:

[0022] For treatment of psoriasis, preferred compounds are those defined by structural formulae P100 to P106 as follows:

[0023] For treatment of osteoporosis, preferred compounds are those defined by structural formulae P101 and P200 to P206, as follows:

[0024] The salts of the Active Ingredients are an additional aspect of the invention. The skilled artisan will also appreciate that the family of compounds include acidic and basic members and that the present invention includes pharmaceutically acceptable salts thereof.

[0025] In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, ammonium, calcium, magnesium, aluminum, zinc, and the like. Sodium and potassium salts are particularly preferred. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. For example, a carboxylic acid substituent on the compound may be selected as -CO₂H and salts may be formed by reaction with appropriate bases (e.g., NaOH, KOH) to yield the corresponding sodium and potassium salt.

[0026] Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Phar. Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, choline, clavulanate, citrate, chloride, chloroprocaine, choline, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate, estolate, esylate, ethylenediamine, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, bromide, chloride, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, malseate, mandelate, meglumine, mesylate, mesviate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate, polygalacturonate, procane, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.

[0027] Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans- isomeric forms of the compounds. The R- and S- isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans- isorners,and all tautomers are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. For example, a chiral column may be used such as those sold by Daicel Chemical Industries identified by the trademarks:
CHIRALPAK AD, CHIRALPAK AS, CHIRALPAK OD, CHIRALPAK OJ, CHIRALPAK OA, CHIRALPAK OB, CHIRALPAK OC, CHIRALPAK OF, CHIRALPAK OG, CHIRALPAK OK, and CHIRALPAK CA-1.

[0028] By another conventional method, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers. These diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization.

[0029] The present invention is also embodied in mixtures of Active Ingredients.

Pharmaceutical Formulations containing the Novel Compounds of the Invention:

[0030] Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of Active Ingredient together with a pharmaceutically acceptable carrier or diluent. The present pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.

[0031] In making the compositions of the present invention, the Active Ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the compound. The Active Ingredient is preferably formulated prior to administration.

[0032] The Active Ingredient may also be delivered by suitable formulations contained in a transderm patch. Alternatively, the Active Ingredient may be delived to a patient by sublingual administration.

[0033] For the pharmaceutical formulations any suitable carrier known in the art can be used. In such formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.

[0034] Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc.

[0035] In powders the carrier is a finely divided solid which is in admixture with finely divided Active ingredient. In tablets the Active Ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of Active Ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.

[0036] Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs.

[0037] The Active Ingredient may be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The Active Ingredient may often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided Active Ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.

Ointment Formulation for Treatment of Psoriasis:

[0038] Treatment of psoriasis is preferably done with topical application by a formulation in the form of a cream, oil, emulsion, paste or ointment containing a therapeutically effective amount of Active Ingredient. The formulation for topical treatment contains from 0.5 to 0.00005 weight percent, preferably from .05 to 0.0005 weight percent, and most preferably from 0.025 to 0.001 of Active Ingredient.

[0039] For example, two semisolid topical preparations useful as vehicles for VDR modulators in treatment and prevention of psoriasis are as follows:

Polyethylene Glycol Ointment USP (p. 2495)

[0040] Prepare Polyethylene Glycol Ointment as follows:

Polyethylene Glycol 3350	400 g.
Polyethylene Glycol 400	600 g.
To make	1000 g.

[0041] Heat the two ingredients on a water bath to 65C. Allow to cool, and stir until congealed. If a firmer preparation is desired, replace up to 100 g of the polyethylene glycol 400 with an equal amount of polyethylene glycol 3350.

Hydrophilic Ointment USP (p. 1216)

[0042] Prepare Hydrophilic Ointment as follows:

Methylparaben	0.25 g.
Propylparaben	0.15 g.
Sodium Lauryl Sulfate	10 g.
Propylene Glycol	120 g.
Stearyl Alcohol	250 g.
White Petrolatum	250 g.
Purified Water	370 g.
To make about	1000 g.

[0043] The Stearyl Alcohol and White Petrolatum are melted on a steam bath, and warmed to about 75C. The other ingredients, previously dissolved in the water are added, warmed to 75C, and the mixture stirred until it congeals.

[0044] For each of the above formulations Active Ingredient is added during the heating step in an amount that is from 0.5 to 0.00005 weight percent, preferably from .05 to 0.0005 weight percent, and most preferably from 0.025 to 0.001 weight percent of the total ointment weight. (Source: - United States Pharmacopoeia 24, United States Pharmacopeial Convention, 1999)

Combination Therapy for Osteoporosis:

[0045] Conventional therapy for osteoporosis includes; (i) estrogens, (ii) androgens, (iii) calcium supplements, (iv) vitamin D metabolites, (v) thiazide diuretics, (vi) calcitonin, (vii) bisphosphonates, (viii) SERMS, and (ix) fluorides (see, Harrison's Principles of Internal Medicine, 13th edition, 1994, published by McGraw Hill Publ., ISBN 0-07-032370-4, pgs.2172-77; the disclosure of which is incorporated herein by reference.). Any one or combination of these conventional therapies may be used in combination with the method of treatment using Active Ingredient as taught herein. For example, in a method of treating osteoporosis, the vitamin D receptor modulator compounds of the invention may be administered separately or simultaneously with a conventional therapy. Alternatively, the Active Ingredient may be combined with conventional therapeutic agents in a formulation for treatment of osteoporosis such as set out below:

A formulation for treating osteoporosis comprising:

Ingredient (A1):

Active Ingredient,

Ingredient (B1):

one or more co-agents that are conventional for treatment osteoporosis selected from the group consisting of:

a. estrogens,

b. androgens,

c. calcium supplements,

d. vitamin D metabolites,

e. thiazide diuretics,

f. calcitonin,

g. bisphosphonates,

h. SERMS, and

i. fluorides.

Ingredient (C1):
optionally, a carrier or diluent.

Typically useful formulations are those wherein the weight ratio of (A1) to (B1) is from 10:1 to 1:1000 and preferably from 1:1 to 1:100.

Combination Therapy for Psoriasis:

[0046] Conventional therapy for psoriasis includes topical glucocorticoids, salicylic acid, crude coal tar, ultraviolet light, and methotrexate (see, Harrison's Principles of Internal Medicine, 13th edition, 1994, published by McGraw Hill Publ., ISBN 0-07-032370-4, pgs.2172-77).. Any one or combination of these conventional therapies may be used in combination with the method of treatment using Active Ingredient as taught herein. For example, in a method of treating osteoporosis, the vitamin D receptor modulator compounds of the invention may be topically administered separately or simultaneously with a conventional therapy. Alternatively, the Active Ingredient may be combined with conventional therapeutic agents in a topically applied formulation for treatment of osteoporosis such as set out below:

A formulation for treating osteoporosis comprising:

Ingredient (A2):

Active Ingredient;

Ingredient (B2):

one or more co-agents that are conventional for treatment psoriasis selected from the group consisting of:

a. topical glucocorticoids ,

b. salicylic acid, or

c. crude coal tar.

Ingredient (C2):
optionally, a carrier or diluent.

Typically useful formulations are those wherein the weight ratio of (A2) to (B2) is from 1:10 to 1:100000 and preferably from 1:100 to 1:10000.

Methods of Using the Compounds of the Invention:

[0047] Generic disease states benefited by treatment with t Active Ingredient include, but are not limited to:

disease states characterized by abnormal calcium regulation

disease states characterized by abnormal cell proliferation

disease states characterized by abnormal immune response

disease states characterized by abnormal dermatological conditions disease states characterized by neurodegenerative condition

disease states characterized by inflammation

disease states characterized by vitamin D sensitivity

disease states characterized by hyperproliferative disorders

[0048] Specific disease states benefited by treatment with Active Ingredient include, but are not limited to:

Abscess

Acne

Adhesion

Actinic keratosis

Alopecia

Alzheimer's disease

Bone maintenance in zero gravity

Bone fracture healing

Breast cancer

Skin cancer

Crohn's disease

Colon cancer

Type I diabetes

Host-graft rejection

Hypercalcemia

Type II diabetes

Leukemia

Multiple sclerosis

Myelodysplastic syndrome

Insufficient sebum secretion

Osteomalacia

Osteoporosis

Insufficient dermal firmness

Insufficient dermal hydration

Psoriatic arthritis

Prostate cancer

Psoriasis

Renal osteodystrophy

Rheumatoid arthritis

Scleroderma

Systemic lupus erythematosus

Ulcerative colitis

Wrinkles

[0049] Particularly preferred is the treatment of psoriasis and osteoporosis by administration to a mammal (including a human) of a therapeutically effective amount of Active Ingredient. By "therapeutically effective amount" it is meant that quantity of a compound of the invention prevents, removes or significantly reduces the deleterious effects of a disease state in mammals, including humans.

[0050] The specific dose of Active Ingredient administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a pharmaceutically effective amount typically in the range of from about 0.0001 mg/kg/day to about 50 mg/kg/day of body weight of an active compound of this invention. Preferably the dose of compounds of the invention will be from 0.0001 to 5 mg/kg/day of body weight.

[0051] Preferably the Active Ingredient or pharmaceutical formulations containing Active Ingredient are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active Ingredient in a unit dose of composition may be varied or adjusted from about 0.0001 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it is necessary to make routine variations to the dosage depending on the age and condition of the patient. The compounds of the inventiion may be administered by a variety of routes including oral, aerosol, rectal, transdermal, sublingual, subcutaneous, intravenous, intramuscular, and intranasal. The dosage will also depend on the route of administration.

Examples

General Experimental Conditions:

[0052] The starting material/intermediate is the compound from the immediate preceding experimental unless otherwise indicated.

[0053] All reactions are performed under nitrogen/argon atmosphere, in a stirred reaction vessel, and at room temperature unless indicated otherwise.

[0054] Unless otherwise indicated, the organic layer is MgSO4/Na2SO4 dried is defined as stirring the solution with a dessicant for 5-15 m and filtering off the dessicant to give an anhydrous filtrate.

[0055] For analogous multi-step reaction procedures, the yield is given either for the ultimate step or overall multi-steps as indicated.

[0056] Solutions are "concentrated" at a range of 25-75 °C with reduced pressure. in-vacuo- 25-75 °C; 0.05 to 1 mm

[0057] Unless otherwise indicated, "the residue is chromatographed" is defined as silica gel chromatography of residue with moderate nitrogen pressure (flash chromatography) or a medium pressure chromatography systems using a silica gel to crude product ratio of ∼10-100.

[0058] Thin layer chromatography is performed with silica gel plates with UV and/or appropriate staining solution.

[0059] NMR spectra are obtained with either 300 or 400 mHz spectrometer.

[0060] NMR - denotes NMR spectrum is consistent with assigned structure.

[0061] HRMS - high resolution mass spectrum

[0062] ES-MS - electrospray mass spectrum

Abbreviations:

[0063] 

Aq - aqueous

d-day

eq - equivalent

h - hour

m - minute

satd - saturated

disp - dispersion

quant - quantitative

rt for retention time (both small caps to minimize confusion with RT)

RT - room temperature

Chemical Definitions:

[0064] 

BBr3 - boron tribromide

BF3-OEt2 - boron trifluoride etherate

BnBr - benzyl bromide

CH2Cl2-dichloromethane

CH3CN - acetonitrile

CO-carbon monoxide

Dess-Martin reagent- 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one

DIBAlH - Diisobutyl Aluminum Hydride

DMAP - 4-(dimethylamino)pyridine

DMF -N,N-dimethylformamide

DMSO - dimethylsulfoxide

DPPB -1,4-bis(diphenylphosphino)butane

DPPF - dichloro[1,1 '-bis(diphenylphosphino)ferrocene

EDCI - 3-Ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride

Et3N - triethylamine

EtMgBr- ethyl magnesium bromide

EtOAc - ethyl acetate

EtOH - ethanol

H2NCH2CO2Me - methyl glycinate

Hept - heptane

Hex - hexanes

HN(OMe)Me - N-methyl-O-methyl hydroxylamine

HNMe2 - dimethyl amine

HATU - O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HOAT- 7-aza-1-hydroxybenzotriazole

HOBT- 1-hydroxybenzotriazole

K2CO3 - potassium carbonate

KOH - potassium hydroxide

LAH - lithium aluminum hydride

LiHMDS - lithium hexamethyldisilazide

mCPBA - meta-chloroperbenzoic acid

MeI - methyl iodide

MeOH - methanol

NaBH4 - sodium borohydride

MgSO4- magnesium sulfate

NaH - sodium hydride

NaHCO3-sodium bicarbonate

NaI - sodium iodide

Na2SO4- sodium sulfate

NH4Cl- ammonium chloride

NMO - 4-methylmorpholine N-oxide

NMP - N-methylpyrrolidin-2-one

Na-S-R3 - sodium alkylmercaptide

PBr3 - phosphorus tribromide

Pd(DPPF) - palladium dichloro[1,1'-bis(diphenylphosphino)ferrocene

Pd(OAc)2 - palladium (II) acetate

Pd(TPP)4 - palladium tetrakistriphenylphosphine

Pd-C - palladium on carbon

(PhO)2P(O)N3 - diphenyl phosphorus azide

pTSA - para-toluenesulfonic acid

Pyr - pyridine

Red-Al- sodium bis(2-methoxyethoxy)aluminum hydride

R2MgBr - alkyl magnesium bromide

R3MgBr - alkyl magnesium bromide

R5MgBr - alkyl magnesium bromide

R2S(O)2NH2 - alkyl sulfonamide

TBAF- tetrabutylammonium fluoride

TBSCl- tert-butyldimethylsilyl chloride

tBuC(O)CH2Br- 1-bromopinacolone

Tf2O - triflic anhydride

TFA - trifluoroacetic acid

THF - tetrahydrofuran

TPAP - tetrapropylammonium perruthenate

Zn(OTf)2 - zinc trifluoromethane sulfonate.

[0065] Example 68 is provided for reference purposes.

Example 1

Preparation of 3'-[4-(2-Oxo-3,3-dimethylbutoxy-3-methylphenyl)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0066] 

A. 2-(t-Butyldimethylsilyloxy)-5-bromotoluene.

[0067] 

[0068] To a 0 °C mixture of 2-hydroxy-5-bromotoluene(48.63 g, 260 mmol), DMF (260 ml), imidazole (18.58 g, 273 mmol) is added t-butyldimethylsilyl chloride (41.15 g, 273 mol) in portions. After stirring for 30 m, the reaction is warmed to RT and stirred for 16 h. The reaction mixture is poured into ice/water (1.251) and extracted with Et₂O. The organic layer is washed with water (2X100 ml), 1N NaOH (2X5 ml), water, brine, MgSO₄ dried, concentrated, chromatographed (hex), and azeotroped with toluene to give the title compound as an oil (75.7 g, 97%)
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.21 (s, 6H), 0.99 (s, 9H), 2.15 (s, 3H), 6.77 (d, J = 8.3 Hz, 1H), 7.25 (dd, J = 6.8, 8.3 Hz, 1H), 7.37 (s, 1H).
EI-MS: 300,302

B. 3'-[4-(t-Butyldimethylsilyloxy)-3-methylphenyl]pentan-3-ol.

[0069] 

[0070] Magnesium turnings (6 g, 248 mmol) is vigorously stirred under nitrogen for 18 h. To the magnesium turnings is added THF (600 ml) and I₂ (100 mg, 0.39 mmol). This is followed by dropwise addition of 2-(t-butyldimethylsilyloxy)-5-bromotoluene (60 g, 200 mmol) in THF (500 ml) and at the same time the reaction is gradually heated by setting the oil bath to 70 °C. After half of the addition of the 2-(t-butyldimethylsilyloxy)-5-bromotoluene/THF is complete, the mixture is heated to 90 °C for 2.5 h. The mixture is allowed to cool to RT and then cooled to 0 °C. To this mixture is added 3-pentanone (21.2 ml, 200 mmol), warmed to RT, and then heated to 50°C for 3 h. After cooling, the reaction is diluted with Et₂O and water, and quenched with 1N HCl to pH 7. The mixture is partitioned and the organic layer is washed with water, Na₂SO₄ dried, concentrated, chromatographed (1.25 kg silica gel, 40% CH₂Cl₂/Hex to 70% CH₂Cl₂/Hex; rf: 0.3) to give the title compound as an oil (44.3 g, 72%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.20 (s, 6H), 0.64 (t, J = 7.8 Hz, 6H), 1.00 (s, 9H), 1.67 (m, 4H), 2.15 9s, 3H), 4.38 (s,1H), 6.70 (d, J = 8.8 Hz, 1H), 7.04 (dd, J = 8.3, 2.0 Hz, 1H), 7.14 (d, J = 2.0Hz, 1H).
EI-MS: 308.37

C. 3'-[4-(Hydroxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane.

[0071] 

[0072] To a -78°C mixture of 3'-[4-(t-butyldimethylsilyloxy)-3-methylphenyl]pentan-3-ol (44 g, 142 mmol) and 3-methylthiophene (83 ml, 854 mmol) is added BF₃-Et₂O (180 ml, 1.42 mol). After stirring for 45 m, the reaction is placed in a 0 °C bath, allowed to warm to RT and stirred for 6 h. The reaction is poured into Et₂O/water and washed with 5N HCl. The organic layer is washed with water, Na₂SO₄ dried, concentrated, and chromatographed (1.5 kg SiO₂, 70% CHCl₃/hex) to give the title compound (37 g, 95%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.63 (t, J = 7.3 Hz, 3H), 2.01 (m, 4H), 2.08 (s, 3H), 2.16 (s, 3H), 6.67 (m, 2H), 6.88 (m, 2H), 6.93 (d, J = 1.9 Hz, 1H), 9.10 (s, 1H). High Res. EI-MS: 274.1389; calc. for C₁₇H₂₂OS: 274.1391

D. 3'-[4-(Benzyloxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane.

[0073] 

[0074] To a 0 °C mixture of 3'-[4-(hydroxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane (7.1 g, 25.9 mmol) and DMF (60 ml) is added 60% NaH disp (1.1 g, 28.5 mmol) and stirred for 15 m. The reaction is added benzyl bromide (3.4 ml, 28.5 mmol), warmed to RT and stirred overnight. The reaction is concentrated in-vacuo and partitioned between Et₂O/1N HCl. The organic layer is washed with water, dried with Na₂SO₄, concentrated, and chromatographed (20% CHCl₃/hex to 30% CHCl₃/hex) to give the title compound (8.7 g, 92%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.61 (t, J = 7.3 Hz, 6H), 1.95-2.07 (m, 4H), 2.13 (s, 6H), 5.05 (s, 2H), 6.65 (d, J =1.5 Hz, 1H), 6.86 (m, 2H), 7.01 (m, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.38 (m, 2H), 7.44 (d, J = 6.8 Hz, 2H).
High Res. EI-MS: 364.187S; calc. for C₂₄H₂₈OS: 364.1861

E. 3'-[4-(Benzyloxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0075] 

concentrated, and chromatographed (10% EtOAc/hex) to give th e title To a-78 °C mixture of 3'-[4-(benzyloxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane (7.7 g, 21 mmol) and THF (50 ml) is added 1.6 M n-BuLi/hex (1.6 ml, 25.3 mmol) and warmed to 0 °C for 2 m. The reaction is cooled to -78 °C, added methyl chloroformate (1.7 ml, 25 mmol) and wanned to RT over 2 h. The reaction is added Et₂O, quenched with 1N HCl, and partitioned. The organic layer is washed with brine, Na₂SO₄ dried,compound (4.8 g, 54%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 2.02-2.07 (m, 4H), 2.14 (s, 3H), 2.40 (s, 3H), 3.69 (s, 3H), 5.06 (s, 2H), 6.82 (s, 1H), 6.92 (d, J = 8.8 Hz, 1H), 7.03 (m, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.38 (t, J = 7.3 Hz, 2H), 7.44 (t, J = 7.3 Hz, 2H).
High Res. ES-MS: 423.2011; calc. for C₂₆H₃₀O₃S+H: 423.1994

F. 3'-[4-(Hydroxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl] entane.

[0076] 

[0077] A mixture of 3'-[4-(benzyloxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (290 mg, 0.686 mmol), 10% Pd/C (1.6 g, 1.5 mmol), EtOH (3 ml), and EtOAc (3 ml) is hydrogenated overnight at atmospheric pressure. The reaction is filtered through diatomaceous earth with EtOH/EtOAc wash, concentrated, and chromatographed (CH₂Cl₂ to 10% EtOAc/CH₂Cl₂) to give the title compound (220 mg, quant).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.61 (t, J = 7.3 Hz, 6H), 1.98-2.07 (m, 4H), 2.05 (s, 3H), 2.39 (s, 3H), 3.69 (s, 3h), 6.66 (d, J= 8.3 Hz, 1H), 6.79 (s, 1H), 6.86 (dd, J = 8.3, 2.4 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 9.15 (s, 1H).
High Res. ES-MS: 333.1528; calc. for C₁₉H₂₄O₃S+H: 333.1524

G. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0078] 

[0079] To a mixture of 3'-[4-(hydroxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (210 mg, 0.63 mmol) and DMF (2 ml) is added 60% NaH disp (25 mg, 0.63 mmol) and warmed to RT. The reaction is cooled to 0 °C, added 3,3-dimethyl-1-bromo-2-butanone (85 ul, 0.63 mmol), warmed to RT, and stirred overnight. The mixture is concentrated and partitioned between Et₂O/1N HCl. The organic layer is washed with water, dried with Na₂SO₄, and chromatographed (10% EtOAc/hex to 20% EtOAc/hex) to give the title compound (230 mg, 85%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.61 (t,J = 7.3 Hz, 6H), 1.15 (s, 9H), 2.01-2.08 (m, 4H), 2.14 (s, 3H), 2.40 (s, 3H), 3.69 (s, 3H), 5.08 (s, 2H), 6.60 (d, J = 8.3 Hz, I H), 6.82 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 7.00 (s, 1H).
High Res. ES-MS: 453.2072; calc, for C₂₅H₃₄O₄S+Na: 453.2076

Example 2

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0080] 

[0081] To a 0 °C mixture of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (215 mg, 0.5 mmol) and MeOH (2 ml) is added NaBH₄ (28 mg, 0.75 mmol) and warmed to RT. The reaction is concentrated and partitioned between Et₂O/1N HCl. The organic layer is washed with water, dried with Na₂SO₄, and concentrated to give the title compound (220 mg, quant).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.90 (s, 9H), 1.99-2.08 (m, 4H), 2.11 (s, 3H), 2.40 (s, 3H), 3.44 (m, 1H), 3.69 (s, 3H), 3.75 (dd, J = 7.3, 10.2 Hz, 1H), 4.03 (dd, J = 3.4, 10.2 Hz, 1H), 4.79 (d, J = 5.4 Hz, 1H), 6.81 (s, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.98 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H).
High Res. ES-MS: 450.2674; calc. for C₂₅H₃₆O₄S+NH₄: 450.2678

Example 3

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-carboxyl-4-niethylthiophen-2-yl]pentane.

[0082] 

[0083] To a mixture of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (200 mg, 0.46 mmol), EtOH (1.5 ml), and water (0.5 ml) is added KOH (200 mg, 3.56 mmol). The reaction is heated to 70°C for 4 h. The mixture is concentrated, partitioned between 1:1 Et₂O:EtOAc and 1N HCl. The organic layer is washed with 1N HCl, Na₂SO₄ dried, and concentrated to give the title compound (200 mg, quant).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.90 (s, 9H), 1.97-2.09 (m, 4H), 2.11 (s, 3H), 2.37 (s, 3h), 3.44 (m, 1H), 3.74 (dd, J = 7.3, 10.2 Hz, I H), 4.01 (dd, J = 3.4, 10.2 Hz, 1H), 4.78 (d,J = 5.4 Hz, 1H), 6.76 (s, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.98 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 12.58 (br s, 1H).
High Res. ES-MS: 436.2518; calc. for C₂₅H₃₆O₄S+NH₄: 436.2521

Example 4

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-(dimethylaminocarbonyl)-4-methylthiophen-2-yl]pentane.

[0084] 

[0085] To a 0 °C mixture of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-carboxyl-4-methylthiophen-2-yl]pentane (175 mg, 0.42 mmol) and Et₃N (61 ul, 0.44 mmol) is added (PhO)₂P(O)N₃ (92 ul, 0.43 mmol). The reaction is warmed to RT and stirred for 30 m. After cooling to 0 °C, the reaction is added DMAP (56 mg, 0.46 mmol) and 2M HNMe₂/THF (0.46 ml, 0.92 mmol). The mixture is warmed to RT and stirred for 2 h. The reaction is concentrated and partitioned between Et₂O/1N HCI. The organic layer is washed with 1N HCl, Na₂SO₄ dried, and chromatographed (CH₂Cl₂ to 15% EtOAc/CH₂Cl₂) to give the title compound (110 mg, 59%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 1.96-2.06 (m, 4H), 2.09 (s, 3H), 2.11 (s, 3H), 2.90 (s, 6H), 3.44 (m, 1H), 3.73 (dd, J = 7.3, 10.2 Hz, 1H), 4.01 (dd, J = 3.4, 10.2 Hz, 1H), 4.79 (br s,1H), 6.65 (s,1H), 6.82 (d,J = 8.8 Hz, I H), 7.02 (m, 2H).
High Res. ES-MS: 446.2738; calc. for C₂₆H₃₉NO₃S+H: 446.2729

Example 5:

Preparation of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl] pentane.

[0086] 

A. 2-(3-Hydroxy-3-pentyl)thiophene.

[0087] 

[0088] To a stirred 0 °C mixture of ethyl thiophene-2-carboxylate (3.12 g, 20.0 mmol) in diethyl ether (100 ml) is added 1M ethylmagnesium bromide (60 ml, 60 mmol). The reaction is allowed to warm to RT and stirred for 3 d. The reaction is partitioned between Et₂O and 1N NaHO₃. The organic layer was Na₂SO₄ dried and concentrated to give the title compound (3.4 g, 99%).
H-NMR (ppm, CDCl₃): 7.98 (1H, d, 4.2 Hz), 6.95 (1H, m), 6.85 (1H, d, 3.0 Hz), 1.86 (4H, q, 7.5 Hz), 0.86 (6H, t, 7.5 Hz).

B. 5-(3-Hydroxy-3-pentyl)thiophene-2-carboxylic acid.

[0089] 

[0090] To a -78 °C mixture of 2-(3-hydroxy-3-pentyl)thiophene (0.34 g, 2.0 mmol) in THF (2 ml) is added of 1.6 M n-butyllithium in Hex (2.75 ml, 4.4 mmol). The mixture is allowed to warm to RT and powderized dry ice (CO₂) is added. After one h, the mixture is partitioned between diethyl ether and 1N NaHCO₃. The aqueous layer is washed with ether, acidified with conc. HCl and extracted with ether. The organic layer is Na₂SO₄ dried, filtered, and concentrated to give the title compound (0.236 g, 53%).
H-NMR (ppm, CDCl₃): 7.75 (1H, d, 3.0 Hz), 6.87 (1H, d, 3.0 Hz), 1.86 (4H, q, 5.7 Hz), 0.86 (6H, t, 5.7 Hz).

C. Methyl, 5-(E/Z-2-penten-3-yl)thiophene-2-carboxylate

[0091] 

[0092] To a mixture of 5-(3-hydroxy-3-pentyl)thiophene-2-carboxylic acid 0.236 g (1.05 mmol) and methanol (15 ml) is bubbled HCl gas for a few minutes. The mixture is heated at reflux for 2 h and then concentrated under vacuum. The residue is partitioned between Et₂O and 1N NaHCO₃. The organic layer is Na₂SO₄ dried and concentrated to give the title compound (0.106 g, 62%).

D. 3'-[4-(Hydroxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0093] 

[0094] To a mixture of methyl 5-(E/Z-2-penten-3-yl)thiophene-2-carboxylate (0.106 g, 0.65 mmol) and o-cresol (0.282 g, 2.61 mmol) in a few drops of methylene chloride is added of BF3 etherate (37 mg, 0.26 mmol). The mixture is stirred overnight and partitioned between Et₂O and 1N NaHCO₃. The organic layer is Na₂SO₄ dried, concentrated, and excess o-cresol is distilled off (73 °C/0.10 mm). The residue is chromatographed (7.5% to 10% EtOAc/hex) to give the title compound (0.104 g, 50%).
H-NMR (ppm, CDCl₃): 7.62 (1H, d, 3.0 Hz), 6.96 (1H, s), 6.94 (1H, d, 6.0.Hz), 6.78 (1H, d, 3.0 Hz), 6.65 (1H, d, 6.0 Hz), 4.60 (1H, s), 3.82 (3H, s), 2.19 (3H, s), 2.10 (4H, q, 5.7 Hz), 0.69 (6H, t, 5.7 Hz).
LC/MS: 319.2 (M+1).

E. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0095] 

[0096] To a stirred 0 °C mixture of 60% disp NaH (15.7 mg, 0.39 mmol, hex washed) is added 3'-[4-(hydroxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (100 mg, 0.31 mmol) in DMF (2:0 ml). The resulting mixture is added 1-chloropinacolone (46 mg, 0.34 mmol) with a crystal of KI. The reaction is allowed to warm to RT and stirred overnight. The mixture is partitioned between Et₂O and 1N NaHCO₃. The organic layer is Na₂SO₄ dried, filtered, concentrated, and chromatographed (on 4g of silica gel with 5% EtOAc/hex) to give the title compound (0.114 g, 87%).
H-NMR (ppm, CDCl₃): 7.62 (1H, d, 3.0 Hz), 6.99 (1H, s). 6.97 (1H, d, 6.0 Hz), 6.77 (1H, d, 3.0 Hz), 6.50 (1H, d, 6.0 Hz), 4.83 (2H, s), 3.82 (3H, s), 2.24 (3H, s), 2.10 (4H, q, 5.7 Hz), 1.24 (9H, s), 0.68 (6H, t, 5.7 Hz).
LC/MS: 417.3 (M+1).

F. 3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0097] 

[0098] To a mixture of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (28 mg, 0.067 mmol) and 95% EtOH (1 ml) is added NaBH₄ (3.8 mg, 0.1 mmol). After stirring overnight, the reaction is added acetone (several drops) and partitioned between CH₂Cl₂ and 1N NaHCO₃. The organic layer is washed with water, Na₂SO₄ dried, and concentrated to give the title compound (23 mg, 82%).
H-NMR (ppm, CDC13): 7.62 (1H, d, 2.7 Hz), 7.02.(1H, d, 6.0 Hz), 6.98 (1H, s), 6.78 (1H, d, 2.6 Hz), 6.71 (1H, d, 6.0 Hz), 4.06 (1H, d, 8.2 Hz), 3.86 (1H, d, 8.4 Hz), 3.82 (3H, s), 3.70 (1H, d, 8.2 Hz), 2.18 (3H, s), 2.10 (4H, q, 6.0 Hz), 1.00 (9H, s), 0.69 (6H, t, 5.8 Hz).
LC/MS: 418.2 (M+).

Example 6A and Example 6B:

Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0099] 

[0100] A mixture of racemic 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (1.4 g, 3.25 mmol) is chromatographed with a ChiralPak AD column to give enantiomer 1, Example 6A (666 mg, 48%) and enantiomer 2, Example 6B (686 mg, 49%) .

Enantiomer 1, Example 6A

[0101] HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/85% heptane; I ml/m (flow rate);
rt = 5.8 m
¹NMR (300MHz, DMSO-d₆) equivalent to Example 2.
High Res. ES-MS: 455.2231; calc. for C₂₅H₃₆O₄S+Na: 455.2232

Enantiomer 2, Example 6B

[0102] HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/85% heptane; 1 ml/m (flow rate); rt = 9.8 m ¹NMR (300MHz, DMSO-d₆) equivalent to Example 2.
High Res. ES-MS: 433.2427; calc. for C₂₅H₃₆O₄S+H: 433.2413

Example 7:

Preparation of enantiomer 1 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-(5-carboxy-4-methylthiophen-2-yl]pentane.

[0103] 

[0104] Using a procedure analogous to Example 3, enantiomer 1 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (Example 6A) gives the title compound as a white foamy solid (440 mg, quant.).
¹NMR (300MHz, DMSO-d₆) equivalent to Example 3.
High Res. ES-MS: 441.2073; calc. for C₂₄H₃₄O₄S+Na: 441.2076

Example 8:

Preparation of enantiomer 2 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-carboxy-4-methylthiophen-2-yl]pentane.

[0105] 

[0106] Using a procedure analogous to Example 3, enantiomer 2 (Example 6B) of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane gives the title compound as a white foamy solid (440 mg, quant.).
¹NMR (300MHz, DMSO-d₆) equivalent to Example 3.
High Res. ES-MS: 441.2074; calc. for C₂₄H₃₄O₄S+Na: 441.2076

Example 9:

Preparation of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methylsulfonylmethyl-4-methylthiophen-2-yl]pentane.

[0107] 

A. 3'-[4-(Benzyloxy)-3-methylphenyl]-3'-[4-methyl-5-(hydroxymethyl)thiophen-2-yl]pentane.

[0108] 

[0109] To a 0 °C mixture of 3'-[4-(benzyloxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (1.55 g, 3.66 mmol) and THF (15 ml) is added LAH (417 mg, 11 mmol) and warmed to RT. The reaction is heated to 45 °C overnight and then cooled to 0 °C. The mixture is quenched with sat'd Na₂SO₄, diluted with Et₂O, dried with Na₂SO₄ and filtered. After concentration, the residue is chromatographed (CHCl₃) to give the title compound (1.1 g, 76%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.64 (t, J = 7.3 Hz, 6H), 1.96-2.05 (m, 4H), 2.06 (s, 3H), 2.15 (s, 3H), 4.43 (s, 2H), 5.06 (m, 3H), 6.55 (s, 1 H), 6.89 (d, J = 9.3 Hz, 1H), 7.26 (br s, 2H), 7.31 (m, 1H), 7.37 (m, 2H), 7.44 (d, J = 7.8 Hz, 2H).
High Res. ES-MS: 377.1950; calc. for C₂₅H₃₀O₂S+H-H₂O: 377.1939

B. 3'-[4-(Benzyloxy)-3-methylphenyl]-3'-[4-methyl-5-(methylmercaptylmethyl)thiophen-2-yl]pentane.

[0110] 

[0111] To a 0 °C mixture of 3'-[4-(benzyloxy)-3-methylphenyl]-3'-[4-methyl-5-(hydroxymethyl)thiophen-2-yl]pentane (450 mg, 1.1 mmol) and Et₂O (3 ml) is added PBr₃ (113 ul, 1.2 mmol) and stirred for 1 h. The reaction is diluted with Et₂O, washed with water (1 X 5 ml), brine (1 X 5 ml), Na₂SO₄ dried, and concentrated. The resulting solid is dissolved in DMF, cooled to 0 °C, added NaSMe (330 mg, 4.8 mmol), and allowed to warmed RT. After stirring for 2 h, the reaction is concentrated and chromatographed (5% EtOAc/hex) to give the title compound (280 mg, 60%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.63 (t, J = 7.3 Hz, 6H), 1.94-2.05 (m, 4H), 1.97 (s, 3H), 2.07 (s, 3H), 2.15 (s, 3H), 3.75 (s, 2H), 5.06 (s, 2H), 6.56 (s, 1H), 6.90 (d, J= 9.3 Hz, 1H), 7.01 (m, 2H), 7.31 (m, 1H), 7.38 (m, 2H), 7.44 (d, J = 6.8 Hz, 2H).
High Res. ES-MS: 425.1964; calc. for C₂₆H₃₂OS₂+H: 425.1973

C. 3'-[4-(Benzyloxy)-3-methylphenyl]-3'-[4-methyl-5-(methylsulfonylmethyl)thiophen-2-yl]pentane.

[0112] 

[0113] To a 0 °C mixture of 3'-[4-(benzyloxy)-3-methylphenyl]-3'-[4-methyl-5-(methylmercaptylmethyl)thiophen-2-yl]pentane (260 mg, 0.611 mmol) and CHCl₃ (3 ml) is added 50% m=CP8A (465 mg, 1.35 mmol) and stirred for 1.5 h. The reaction is diluted with CHCl₃, washed with satd Na₂CO₃, Na₂SO₄ dried, concentrated, and chromatographed (CHCl₃ to 5% EtOAc/CHCl₃) to give the title compound as a white foamy solid (250 mg, 90%).
¹NMR (400MHz. DMSO-d₆) δ ppm: 0.64 (t, J = 7.3 Hz, 6H), 1.99-2.07 (m, 4H), 2.14 (s, 3H), 2.15 (s, 3H), 2.90 (s, 3H), 4.53 (s, 2H), 5.06 (s, 2H), 6.67 (s, 1H), 6.91 (d, J = 9.3 Hz, 1H), 7.03 (m, 2H), 7.31 (m, 1H), 7.38 (m, 2H), 7.44 (d. J = 7.3 Hz, 2H).
High Res. ES-MS: 474.2126; calc. for C₂₆H₃₂O₃S₂+NH₄: 474.2137

D. 3'-[4-(Hydroxy)-3-methylphenyl]-3'-[4-methyl-5-(methylsulfonylmethyl)thiophen-2-yl]pentane.

[0114] 

[0115] Using a procedure analogous to Example 1F, 3'-[4-(benzyloxy)-3-methylphenyl]-3'-[4-methyl-5-(methylsulfonylmethyl)thiophen-2-yl]pentane gives the title compound as a white foamy solid (160 mg, 81%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.63 (t, J = 7.3 Hz, 6H), 1.94-2.03 (m, 4H), 2.06 (s, 3H), 2.14 (s, 3H), 2.89 (s, 3H), 4.52 (s, 2H), 6.65 (m, 2H), 6.85 (dd, J = 2.4, 8.3 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 9.09 (s, 1H).
High Res. ES-MS: 384.1648; calc. for C₁₉H₂₆O₃S₂+NH₄: 384.1667

E. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methylsulfonylmethyl-4-methylthiophen-2-yl]pentane.

[0116] 

[0117] Using a procedure analogous to Example 1G, 3'-[4-(hydroxy)-3-methylphenyl]-3'-[4-methyl-5-(methylsulfonylmethyl)thiophen-2-yl]pentane gives the title compound (160 mg, 84%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.63 (t, J = 7.3 Hz, 6H), 1.16 (s, 9H), 2.00-2.08 (m, 4H), 2.14 (s, 3H), 2.15 (s, 3H), 2.90 (s, 3H), 4.53 (s, 2H), 5.07 (s, 2H), 6.60 (d, J = 8.3 Hz, 1H), 6.67 (s, 1H), 6.97 (d, J = 8.3 Hz, 1H), 7.01 (s, 1H).
High Res. ES-MS: 482.2397; calc. for C₂₅H₂₆O₄S₂+NH₄: 482.2399

Example 10:

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-metylsulfonylmethyl-4-methylthiophen-2-yl]pentane.

[0118] 

[0119] Using a procedure analogous to Example 2,3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methylsulfonylmethyl-4-methylthiophen-2-yl]pentane gives the title compound as a white foamy solid (440 mg, quant).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.92 (s, 9H), 1.97-2.08 (m, 4H), 2.12 (s, 3H), 2.14 (s, 3H), 2.89 (s, 3H), 3.45 (m, 1H), 3.76 (dd, J = 7.3, 9.8 Hz, 1H), 4.02 (dd, J = 2.9, 9.8 Hz, 1H), 4.52 (s, 2H), 4.78 (d, J = 5.4 Hz, 1H), 6.66 (s, 1H), 6.82 (d, J = 8.3 Hz, 1H), 7.01 (m, 2H).
High Res. ES-MS: 484.2553; calc. for C₂₅H₃₈O₄S₂+NH₄: 484.2555

Example 11A and 11B

Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methylsulfonylmethyl-4-methylthiophen-2-yl]pentane.

[0120] 

[0121] A racemic mixture of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methylsulfonylmethyl-4-methylthiophen-2-yl]pentane is chromatographed with a Chiralcel AD column to give enantiomer 1, Example 11A (205 mg, ~50%) and enantiomer 2, Example 11B (150 mg, 38%) .

Enantiomer 1, Example 11A

[0122] HPLC: Chiralcel AD (4.6X250 mm); 40% IPA/60% hept; 1 ml/m (flow rate); rt = 9.86 m; 260 nm.
¹NMR equivalent to Example 10.
High Res. ES-MS: 489.2127; calc. for C₂₅H₃₈O₄S₂+Na: 489.2109.

Enantiomer 2, Example 11B

[0123] HPLC: Chiralcel AD (4.6X250 mm); 40% IPA/60% hept; 1 ml/m (flow rate); rt = 12.64 m; 260 nm.
¹NMR equivalent to Example 10.
High Res. ES-MS: 489.2132; calc. for C₂₅H₃₈O₄S₂+Na: 489.2109.

Example 12

Alternative preparation of 3'-[4-(2-oxo-3,3-dimethylbutoxy-3-methylphenyl)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (Example 1).

[0124] 

A. 4-Hydroxy-3-methylbenzoic acid methyl ester.

[0125] 

[0126] To a mixture of 3-methyl-4-hydroxybenzoic acid (342 g, 2.24 mol) in MeOH (3.5 1) is bubbled HCl (g) for 5 m. The mixture is stirred for 12 h at RT. The reaction is concentrated to give the title compound (372 g, quant).
H-NMR (ppm, CDCl₃): 7.82 (1H, s), 7.78 (1H, dd, ), 6.80 (1H, d), 3.86 (3H, s), 2.22 (3H, s).

B. 3'-[4-hydroxy-3-methylphenyl]pentan-3-ol].

[0127] 

[0128] To a 0 °C mixture of 4-hydroxy-3-methylbenzoic acid methyl ester (373 g, 2.24 mol) in THF (61) is added 3.0 M EtMgBr/Et₂O (2.3 1, 6.93 mol) over 3 h. The mixture is warmed to 40 °C for 2 h and cooled to 0 °C. Saturated NaHCO₃ is added slowly until gas evolution ceases and the reaction is partitioned between EtOAc/water. The organic layer is washed with brine, water, MgSO₄ dried and concentrated. The residue is dissolved in CH₂Cl₂, dried with Na₂SO₄ and concentrated to give the title compound (440 g, quant). H- NMR (ppm, CDCl₃): 7.06 (1H, s), 7.02 (1H, dd), 6.78 (1H, d), 4.60 (1H, s), 2.24 (3H, s), 1.80 (4H, m), 0.77 (6H, t).

C. 3'-[4-(Hydroxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane.

[0129] 

[0130] To a -78 °C mixture of 3'-[4-hydroxy-3-methylphenyl]pentan-3-ol] (415 g, 2.13 mol), 3-methyltliophene (627 g, 6.39 mol) and CH₂Cl₂ (61) is added BF₃- Et₂O (1.81 kg, 12.8 mol), maintaining the temperature below -75 °C. The reaction is warmed to RT for 3 h and cooled to 0 °C. Saturated NaHCO₃ is added until the gas evolution ceases and the mixture is partitioned with water. The organic layer is dried with Na₂SO₄, concentrated and chromatographed (EtOAc/hex) to give the title compound (425 g, 73%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.63 (t, J = 7.3 Hz, 3H), 2.01 (m, 4H), 2.08 (s, 3H), 2.16 (s, 3H), 6.67 (m, 2H), 6.88 (m, 2H), 6.93 (d, J = 1.9 Hz, 1H), 9.10 (s, 1H). High Res. EI-MS: 274.1389; calc. for C₁₇H₂₂OS: 274.1391

D. 3'-[4-(t-Butyldimethylsilyloxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane.

[0131] 

[0132] To a mixture of 3'-[4-(hydroxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane (5.00g, 187.2 mmol) and t-butyldimethylsilyl chloride (2.75g, 18.2 mmol) in CH₂Cl₂ (100 ml) is added imidazole (1.24g, 18.2 mmol). The reaction is stirred for 24 h at RT. The mixture is diluted with Hex (100 ml), filtered and concentrated. The concentrate is suspended in Hex (100 ml), filtered and concentrated to give the title compound as an oil (6.91 g, 98%).
H-NMR (ppm, CDCl₃): 7.05 (1H, d, 2.0 Hz), 6.97 (1H, d, 9.0 Hz), 6.72 (1H, d, 1.1 Hz), 6.68 (1H, d, 8.3 Hz), 6.62 (1H, d, 1.3 Hz), 2.23 (3H, s), 2.20 (3H, s), 2.10 (4H, m), 1.03 (9H, s), 0.72 (6H, t, 7.3 Hz), 0.23 (6H, s).

E. 3'-[4-(t-Butyldimethylsilyloxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0133] 

[0134] To a -78 °C mixture of 3'-[4-(t-butyldimethylsilyloxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane.(6.75 g, 17.4 mmol) and THF (100 ml) is added 2.5 M n-BuLi/hex (7.64 ml, 19.1 mmol). The mixture is stirred for 25 m and warmed to 0 °C over 15 m. The reaction is cooled to -78 °C, added methyl chloroformate (1.48 ml, 19.1 mmol) and warmed to RT overnight. To the reaction is added water (25 ml). The mixture is concentrated and partitioned with CH₂Cl₂/ water. The organic layer is concentrated to yield the title compound (7.8g, quant.).
H-NMR (ppm, CDCl₃): 6.99 (1H, d, 2.0 Hz), 6.94 (1H, dd, 2.3, 8.5 Hz), 6.67 (1H, d, 8.5 Hz), 6.62 (1H, s), 3.77 (3H, s), 2.49 (3H, s), 2.17 (3H, s), 2.09 (4H, m), 1.01 (9H, s), 0.70 (6H, t, 7.3 Hz), 0.22 (6H, s).

F. 3'-[4-Hydroxy-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0135] 

[0136] To a 0 °C mixture of 3'-[4-(t-butyldimethylsilyloxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (130 g, 292 mmol) and THF (1 L) is added 1.0 M TBAF/THF (292 ml, 292 mmol) over 20 m. The reaction is warmed to RT and stirred for 1 d. The mixture is concentrated and partitioned with CH₂Cl₂/ water. The organic layer is concentrated and chromatographed (EtOAc/hex) to give the title compound (40.2 g, 41%).
H-NMR (ppm, CDCl₃): 6.97 (1H, s), 6.95 (1H, d, 7.5 Hz), 6.69 (1H, d, 8.2 Hz), 6.61 (1H, s), 4.95 (1H, br s), 3.80 (3H, s), 2.47 (3H, s), 2.21 (3H, s), 2.08 (4H, m), 0.91 (3H, s), 0.70 (6H, t, 7.3 Hz).

G. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0137] 

[0138] To a mixture of 3'-[4-hydroxy-3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (14.5 g, 43.6 mmol), acetone (200 ml) and K₂CO₃ (12.1 g, 87.2 mmol) is added 3,3-dimethyl-1-chloro-2-butanone (5.73 ml, 43.6 mmol). The mixture is stirred overnight, refluxed for 9 h and cooled to RT overnight. The reaction is filtered and concentrated to give the title compound (18.8 g, quant.). H-NMR,(ppm, CDCl₃): 6.99 (2H, m), 6.60 (1H, s), 6.51 (1H, d, 8.5 Hz), 4.84 (2H, s), 3.79 (3H, s), 2.47 (3H, s), 2.25 (3H, s), 2.08 (4H, m), 1.25 (9H, s), 0.70 (6H, t, 7 Hz).

Example 13

Preparation of 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylsulfonylmethyloxy)-3-methylphenyl]pentane.

[0139] 

H. 3'-[5-(3-Oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-benzyloxy-3-methylphenyl]pentane.

[0140] 

[0141] To a 0 °C mixture of 3'-[4-(benzyloxy)-3-methylphenyl]-3'-[4-methyl-5-(hydroxymethyl)thiophen-2-yl]pentane (900 mg, 2.3 mmol) and Et₂O (7 ml) is added PBr₃ (240 ul, 2.5 mmol) and stirred for 1.5 h. The reaction is diluted with Et₂O, washed with water (10 ml), brine (10 ml), Na₂SO₄ dried, and concentrated. The resulting residue is dissolved in THF (4 ml) and cooled to -78 °C to afford the bromide/THF solution. In a separate flask is charged with 1M LiHMDS (4.6 ml, 4.6 mmol), cooled to -78 C, and added pinacolone (570 ul, 4.6 mmol). The reaction is stirred for 1.5 h, warmed to -50 C and transferred (via syringe) to the -78 °C solution of bromide/THF. The reaction is warmed to RT with a cold water bath. After stirring for 15 m, the reaction is diluted with Et2O and washed with IN HCI. The organic layer is Na2SO4 dried and chromatographed (30% CHCl3/hex to 80% CHCl3/hex) to give the title compound (900 mg, 82%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 1.00 (s, 9H), 1.93-2.04 (m, 4H), 2.15 (s, 3H), 2.71 (m, 2H), 2.80 (m, 2H), 5.08 (s, 2H), 6.55 (s, 1H), 6.90 (d, J = 8.3 Hz, 1H), 7.01 (m, 2H), 7.34 (d, J = 7.3 Hz, 1H), 7.41 (m, 2H), 7.46 (d, J = 7.8 Hz, 2H).
High Res. ES-MS: 477.2830; calc. for C₃₁H₄₀O₂S+H: 477.2827.

I. 3'-[5-(3-Oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-hydroxy-3-methylphenyl]pentane.

[0142] 

[0143] Using a procedure analogous to Example 1F, 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-benzyloxy-3-methylphenyl]pentane gives the title compound (600 mg, 97%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.59 (t, J = 7.3 Hz, 6H), 0.99 (s, 9H), 1.91-1.98 (m, 4H), 2.03 (s, 3H), 2.04 (s, 3H), 2.71 (m, 2H), 2.75 (m, 2H), 6.49 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.82 (d, J= 8.3 Hz, 1H), 6.86 (s, 1H), 9.04 (s, 1H).
High Res. ES-MS: 409.2167; calc. for C₂₄H₃₄O₂S+Na: 409.2177.

J. 3'-[5-(3-Oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylmercaptylmethyloxy)-3-methylphenyl]pentane.

[0144] 

[0145] Using a procedure analogous to Example 1D, 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-hydroxy-3-methylphenyl)pentane and methylmercaptylmethyl chloride give the title compound (440 mg, 73%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.61 (t, J = 7.3 Hz, 6H), 0.98 (s, 9H), 1.93-2.01 (m, 4H), 2.04 (s, 3H), 2.11 (s, 3H), 2.17 (s, 3H), 2.71 (m, 2H), 2.76 (m, 2H), 5.23 (s, 2H), 6.86 (d, J = 8.3 Hz, 1H), 6.98 (m, 2H).
High Res. ES-MS: 469.2230; calc. for C₂₆H₃₈O₂S₂+Na: 469.2211.

K. 3'-[5-(3-Oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylsulfonylmethyloxy)-3-methylphenyl]pentane.

[0146] 

[0147] Using a procedure analogous to Example 9C, 3'-[5-(3-Oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylmercaptylmethylox)-3-methylphenyl]pentane gives the title compound (140 mg, 33%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.61 (t, J = 7.3 Hz, 6H), 0.99 (s, 9H), 1.95-2.02 (m, 4H), 2.04 (s, 3H), 2.17 (s, 3H), 2.71 (m, 2H), 2.76 (m, 2H), 3.04 (s, 3H), 5.24 (s, 2H), 6.53 (s, 1H), 7.01 (m, 3H).
High Res. ES-MS: 501.2129; calc. for C₂₆H₃₈O₄S₂+Na: 501.2109.

Example 14

Preparation of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylsulfonylmethyloxy)-3-methylphenyl]pentane.

[0148] 

[0149] Using a procedure analogous to Example 2, 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methy]thiophen-2-yl]-3'-[4-(methylsulfonylmethyloxy)-3-methylphenyl]pentane gives the title compound (100 mg, quant.).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.11-1.38 (m, 1H), 1.56-1.63 (m, 1H), 1.94-2.01 (m, 4H), 2.04 (s, 3H), 2.18 (s, 3H), 2.52-2.60 (m, 1H), 2.77-2.83 (m, 1H), 2.94-2.97 (m, 1H), 3.04 (s, 3H), 4.38 (d, J = 5.9, 1H), 5.25 (s, 2H), 6.53 (s, 1H), 7.01 (m, 3H).
High Res. ES-MS: 503.2268; calc. for C₂₆H₄₀O₄S₂+Na: 503.2266.

Example 15A and 15B

Preparation of enantiomers of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylsulfonylmethyloxy)-3-methylphenyl]pentane.

[0150] 

[0151] A mixture of racemic 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(methylsulfonylmethyloxy)-3-methylphenyl]pentane is chromatographed with a Chiralcel OD column to give enantiomer 1

[0152] Example 3A (54 mg, 43%) and enantiomer 2, Example 3B (55 mg, 44%) .
Enantiomer 1, Example 3A]
HPLC: Chiralcel OD (4.6X250 mm); 40% IPA/60% heptane; 1 ml/m (flow rate); rt = 8.9 m; 225 nm.
¹NMR equivalent to Example Yee-2.
High Res. ES-MS: 503.2269; calc. for C₂₆H₄₀O₄S₂+Na: 503.2266.
Enantiomer 2, Example 3B
HPLC: Chiralcel OD (4.6X250 mm); ); 40% IPA/60% heptane; 1 ml/m (flow rate); rt = 11.3 m; 225 nm.
¹NMR equivalent to Example 2.
High Res. ES-MS: 503.2280; calc. for C₂₆H₄₀O₄S₂+Na: 503.2266.

Example 17

Preparation of 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylsulfonyloxy)-3-methylphenyl]pentane.

[0153] 

[0154] Using a procedure analogous to Example 1D, 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(hydroxy)-3-methylphenyl]pentane gives the title compound (425 mg, 65%).
TLC: CHCl₃; Rf= 0.4.
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.98 (s, 9H), 1.93-2.15 (m, 4H), 2.05 (s, 3H), 2.24 (s, 3H), 2.72 (m, 2H), 2.77 (m, 2H), 3.40 (s, 3H), 6.57 (s, 1H), 7.11 (d, J = 2.5 Hz, 1H), 7.19 (m, 2H).
High Res. ES=MS: 487.1940; calc. for C₂₅H₃₆O₄S₂+Na: 487.1940.

Example 18

Preparation of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylsulfonyloxy)-3-methylphenyl]pentane.

[0155] 

[0156] Using a procedure analogous to Example 2,3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylsulfonyloxy)-3-methylphenyl]pentane gives the title compound (300 mg, 96%).
TLC: 5% EtOAc/CHCl₃; Rf=0.35.
¹NMR (300MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.35 (m, 1H), 1.62 (m, 1H), 1.95-2.12 (m, 4H), 2.04 (s, 3H), 2.25 (s, 3H), 2.60 (m, 1H), 2.81 (m, 1H), 2.98 (m, 1H), 3.42 (s, 3H), 4.37 (d, J = 6.2 Hz, 1H), 6.59 (s, 1H), 7.13 (dd, J = 2.2, 8.8 Hz, 1H), 7.22 (m, 2H).
High Res. ES-MS: 484.2539; calc. for C₂₅H₃₈O₄S₂+NH₄: 484.2555.

Example 19A and 19B

Preparation of enantiomers of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylsulfonyloxy)-3-methylphenyl]pentane.

[0157] 

[0158] A mixture of racemic 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methylsulfonyloxy)-3-methylphenyl]pentane is chromatographed with a Chiralcel AD column to give enantiomer 1, Example 19A (108 mg, 43%) and enantiomer 2, Example 19B (109 mg, 44%).

Enantiomer 1, Example 19A

[0159] HPLC: Chiralcel AD (4.6X250 mm); 10% IPA/heptane; 1 ml/m (flow rate); rt = 6.85 m; 250 nm.
¹NMR equivalent to Example 18.
High Res. ES-MS: 489.2106; calc. for C₂₅H₃₈O₄S₂+Na: 489.2109.

Enantiomer 2, Example 19B.

[0160] HPLC: Chiralcel AD (4.6X250 mm); 10% IPA/heptane; 1 ml/m (flow rate); rt = 8.00 m; 250 nm.
¹NMR equivalent to Example 18..
High Res. ES-MS: 489.2112; calc. for C₂₅H₃₈O₄S₂+Na: 489.2109.

Example 20

Preparation of 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-methoxycarbonyl-3-methylphenyl]pentane.

[0161] 

A. 3'-[5-(3-Oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(trifluoromethylsulfonyloxy)-3-methylphenyl]pentane.

[0162] 

[0163] To a 0 °C mixture of 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-hydroxy-3-methylphenyl]pentane (2.7 g, 7.0 mmol) and pyridine (8 ml) is added Tf2O (1.3 ml, 7.7 mmol ). The reaction is warmed to RT and stirred overnight. The reaction is diluted with Et20, washed with 1N HCl and brine, Na2SO4 dried, and concentrated. The residue is chromatographed (30 /hex) to give the title compound (2.9 g, 80%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.61 (t, J = 7.3 Hz, 6H), 0.97 (s, 9H), 1.95-2.11 (m, 4H), 2.04 (s, 3H), 2.28 (s, 3H), 2.70 (m, 2H), 2.77 (m, 2H), 6.59 (s, 1H), 7.19 (dd, J = 2.4, 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H).
High Res. ES-MS: 519.1838; calc. for C₂₅H₃₃F₃O₄S₂+H: 519.1851.

B. 3'-[5-(3-Oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-methoxycarbonyl-3-methylphenyl]pentane.

[0164] A mixture of 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(trifluoromethylsulfonyloxy)-3-methylphenyl]pentane (2.65 g, 5.1 mmol), DPPF (554 mg, 1.0 mmol), Pd(OAc)₂ (120 mg, 0.51 mmol), DMF (10 ml), MeOH (2.1 ml) and Et₃N (2.1 ml, 15.3 mmol) is heated in an autoclave at 110 C under CO pressure (1000 psi). After 48 h, the reaction is cooled to RT and diluted with Et2O. The mixture is washed with 5N HCl, water, and Na2SO4 dried and concentrated. The residue is chromatographed (10% EtOAc/hex) to give the title compound (1.86 g, 85%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.61 (t,1= 7.3 Hz, 6H), 0.98 (s, 9H), 1.96-2.12 (m, 4H), 2.04 (s, 3H), 2.47 (s, 3H), 2.71 (m, 2H), 2.78 (m, 2H), 3.79 (s, 3H), 6.56 (s, 1H), 7.15 (m, 2H), 7.71 (d, J = 7.8 Hz, 1H).
High Res. ES-MS: 446.2741; calc. for C₂₆H₃₆O₃S+NH₄: 446.2729.

Example 21

Preparation of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-methoxycarbonyl-3-methylphenyl]pentane.

[0165] 

[0166] Using a procedure analogous to Example 2, 3'-[5-(3-Oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-methoxycarbonyl-3-methylphenyl]pentane gives the title compound (785 mg, 98%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.63 (t. J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.35 (m, 1H), 1.54 (m, 1H), 1.98-2.13 (m, 4H), 2.04 (s, 3H), 2.48 (s, 3H), 2.56 (m, 1H), 2.79 (m, 1H), 2.95 (m, 1H), 3.79 (s, 3H), 4.37 (br s, d, 1H), 6.57 (s, 1H), 7.17 (m, 2H), 7.72 (d, J = 7.8 Hz, 1H).
High Res. ES-MS: 431.2630; calc. for C₂₆H₃₈O₃S+H: 431.2620.

Example 22

Preparation of 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-carboxyl-3-methylphenyl]pentane.

[0167] 

[0168] Using a procedure analogous to Example 3,3'-[5-(3-oxo-4,4-dimethylpentyl). 4-methylthiophen-2-yl]- 3'-[4-methoxycarbonyl-3-methylphenyl]pentane gives the title compound (800 mg, 92%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.98 (s, 9H), 1.96-2.11 (m, 4H), 2.04 (s, 3H), 2.47 (s, 3H), 2.71 (m, 2H), 2.77 (m, 2H), 6.56 (s, 1H), 7.11 (m, 2H), 7.71 (d, J = 8.3 Hz, 1H), 12.64 (s, 1H).
High Res. ES-MS: 415.2297; calc. for C₂₅H₃₄O₃S+H: 415.2307.

Example 23

Preparation of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-carboxyl-3-methylphenyl]pentane.

[0169] 

[0170] Using a procedure analogous to Example 3,3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-methoxycarbonyl-3-methylphenyl]pentane gives the title compound (700 mg, 99%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.36 (m, 1H), 1.58 (m, 1H), 1.96-2.11 (m, 4H), 2.04 (s, 3H), 2.48 (s, 3H), 2.55 (m, 1H), 2.60 (m, 1H), 4.37 (d, J= 6.2 Hz, 1H), 6.58 (s, 1H), 7.17 (m, 2H), 7.73 (d, J = 8.1 Hz, 1H), 12.65 (br s, 1H).
High Res. ES-MS: 439.2322; calc. for C₂₅H₃₆O₃S+Na: 439.2283.

Example 24

Preparation of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane.

[0171] 

[0172] To a mixture of DMAP (256 mg, 2.1 mmol), methyl glycinate hydrochloride (123 mg, 1.01 mmol), EDCI (193 mg, 1.01 mmol) and CH₂Cl₂ (4 ml) is added 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-carboxyl-3-methylphenyl]pentane (350 mg, 0.84 mmol). The reaction is added CH₂Cl₂ (2 ml) and DMF (1 ml). The mixture is stirred for 16 h and concentrated. The residue is diluted with Et₂O, 1N HCl (3X), brine and Na₂SO₄ dried. The organic solution is concentrated and chromatographed (20% EtOAc/CHCl₃ to 50% EtOAc/CHCl₃) to give the title compound (320 mg, 78%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.64 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.35 (m, 1H), 1.57 (m, 1H), 1.98-2.12 (m, 4H), 2.32 (s, 3H), 2.53-2.61 (m, 1H), 2.77-2.84 (m, 1H), 2.95 (m, 1H), 3.65 (s, 3H), 3.94 (d, J = 5.9 Hz, 2H), 4.39 (br s, 1H), 6.56 (s, 1H), 7.11 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 8.62 (t, J = 5.9 Hz, 1H).
ES-MS: 488.2 (M+H).

Example 25A and 25B

Preparation of enantiomers of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane.

[0173] 

[0174] A racemic mixture of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane is chromatographed with a Chiralcel AD column to give enantiomer 1, Example 25A (110 mg, 37%) and enantiomer 2, Example 25B (102 mg, 34%).

Enantiomer 1, Example 25A

[0175] HPLC: Chiralcel AD (4.6X250 mm); 10% IPA/heptane; 1 ml/m (flow rate); rt = 16.90 m; 240 nm.
¹ NMR equivalent to Example 24.
High Res. ES-MS: 488.2812; calc. for C₂₈H₄₁NO₄S+H: 488.2835.

Enantiomer 2, Example 25B.

[0176] HPLC: Chiralcel AD (4.6X250. mm); 10% IPA/heptane; 1 ml/m (flow rate); rt = 20.00 m; 240 mn.
¹NMR equivalent to Example 24.
High Res. ES-MS: 488.2831; calc. for C₂₈H₄₁NO₄S+H: 488.2835.

Example 26

Preparation of isomer 1 of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)4-methylthiophen-2-yl]-3'-[4-(carboxylmethylaminocarbonyl)-3-methylphenyl]pentane.

[0177] 

[0178] Using a procedure analogous to Example 3 but reacted at 50 °C, isomer 1 of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane (Example 13A) gives the title compound (95 mg, 98%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.64 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.34 (m, 1H), 1.58 (m, 1H), 1.97-2.12 (m, 4H), 2.04 (s, 3H), 2.32 (s, 3H), 2.57 (m, 1H), 2.80 (m, 1H), 2.95 (m, 1H), 3.84 (d, J = 6.3 Hz, 1H), 4.38 (br s, 1H), 6.56 (s, 1H), 7.10 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 8.48 (t, J = 6.3 Hz, 1H), 12.47 (br s, 1H).
High Res. ES-MS: 474.2689; calc. for C₂₇H₃₉NO₄S+H: 474.2678.

Example 27

Preparation of isomer 2 of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)4-methylthiophen-2-yl]-3'-[4-(carboxylmethylaminocarbonyl)-3-methylphenyl]pentane.

[0179] 

[0180] Using a procedure analogous to Example 3 except using LiOH at 60 °C, isomer 2 of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(methoxycarbonylmethylaminocarbonyl)-3-methylphenyl]pentane gives the title compound (79 mg, 94%).
¹NMR equivalent to Example 26.
High Res. ES-MS: 474.2672; calc. for C₂₇H₃₉NO₄S+H: 474.2678.

Example 28

Preparation of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(ethoxycarbonylethyl)-3-methylphenyl]pentane.

[0181] 

3'-[5-(3-Hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(trifluoromethylsulfonyloxy)-3-methylphenyl]pentane.

[0182] 

[0183] Using a procedure analogous to Example 8A, isomer 1 of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-hydroxy-3-methylphenyl]pentane gives the title compound (1.1 g, 64%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.63 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.35 (m, 1H), 1.59 (m, 1H), 1.97-2.12 (m, 4H), 2.04 (s, 3H), 2.29 (s, 3H), 2.58 (m, 1H), 2.80 (m, 1H), 2.94 (m, 1H), 4.38 (br s, 1H), 6.59 (s, 1H), 7.21 (dd, J = 2.4, 8.8 Hz, 1H ), 7.26 (m, 2H), 7.33 (d, J = 2.0 Hz, 1H).
High Res. EI-MS: 520.1927; calc. for C₂₅H₃₅F₃O₄S₂: 520.1929,

A. 3'-[5-(3-Hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4- . (ethoxycarbonylethyl)-3-methylphenyl]pentane.

[0184] To a 0 °C mixture of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(trifluoromethylsulfonyloxy)-3-methylphenyl]pentane (1.08 g, 2.07 mmol), Pd(Dppf)2C12 (170 mg, 0.207 mmol), LiCl (350 mg, 8.3 mmol) and THF (1 ml) is added 0.5M of 2-(ethoxycarbonyl)ethylzinc bromide/THF (12.4 ml, 6.21 mmol). The reaction is heated to 60 °C for 1 h and concentrated (to ∼8 ml of volume) with a stream of nitrogen. The reaction is heated under nitrogen for another 15 h. After cooling, the reaction is diluted with Et₂O, quenched with 2.5N HCl, washed with water, Na2SO4 dried, and concentrated. The residue is chromatographed (70% CHCl₃/hex to 100% CHCl₃) to give the title compound (550 mg, 56%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.61 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.14 (t, J = 6.8 Hz, 3H), 1.33 (m, 1H), 1.58 (m, 1H). 1.93-2.19 (m, 4H), 2.04 (s, 3H), 2.22 (s, 3H), 2.51-2.59 (m, 3H), 2.75-2.83 (m, 3H), 2.95 (m, 1H), 4.02 (q, J = 7.3 Hz, 2H), 4.38 (br s, 1H), 6.53 (s, 1H), 6.98 (m, 3H).
High Res. ES-MS: 495.2926; calc. for C₂₉H₄₄O₃S+Na: 495.2909.

Example 29

Preparation of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(2-carboxylethyl)-methylphenyl]pentane.

[0185] 

[0186] Using a procedure analogous to Example 3 but reacted at RT for 45 m, 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(2-ethoxycarbonylethyl)-3-methylphenyl]pentane gives the title compound (450 mg, 95%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.34 (m, 1H), 1.59 (m, 1H), 1.97-2.19 (m, 4H), 2.04 (s, 3H), 2.21 (s, 3H), 2.45 (t, J = 7.3 Hz, 2H), 2.54 (m, 1H), 2.74 (t, J = 8.3 Hz, 2H), 2.79 (m, 1H), 2.96 (m, 1H), 4.38 (br s, 1H), 6.53 (s, 1H), 6.99 (m, 3H), 12.09 (br s, 1H).
ES-MS: 445.3 (M+H).

Example 30A and 30B

Preparation of enantiomers of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(2-carboxylethyl)-3-methylphenyl]pentane.

[0187] 

[0188] A racemic mixture of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-Methylthiophen-2-yl]- 3'-[4-(2-carboxylethyl)-3-methylphenyl]pentane is chromatographed with a Chiralcel AD column to give enantiomer 1, Example 30A (108 mg, 43%) and enantiomer 2, Example 30B (109 mg, 44%).

Enantiomer 1, Example 30A

[0189] HPLC: Chiralcel AD (4.6X250 mm); 0.1% TFA in 5% EtOH/hept; 1 ml/m (flow rate); rt = 8.20 m; 210 nm.
¹NMR (300MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.35 (m, 1H), 1.61 (m, 1H), 1.97-2.10 (m, 4H), 2.04 (s, 3H), 2.22 (s, 3H), 2.47 (m, 2H), 2.56 (m, 1H), 2.77 (m, 3 H), 2.95 (m, 1H), 4.37 (d, J=6.2 Hz, 1H), 6.54 (s, 1H), 7.02 (m, 3H), 12.12 (br s, 1H).
High Res. ES-MS: 462.3054; calc. for C₂₇H₄₀NO₃S+NH₄: 462.3042.

Enantiomer 2, Example 30B.

[0190] HPLC: Chiralcel AD (4.6X250 mm); 0.1% TFA in 5% EtOH/hept; 1 ml/m (flow rate); rt = 10.09 m; 210 nm.
¹NMR equivalent to Example 29.
High Res. ES-MS: 462.3057; calc. for C₂₇H₄₀NO₃S+NH₄: 462.3042.

Example 31

Preparation of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(methoxycarbonylmethoxy)-3-methylphenyl]pentane.

[0191] 

A. 3'-[5-(3-hydroxy-4,4-dimethylpentyl)4-methylthiophen-2-yl]- 3'-[4-hydroxy-3-methylphenyl]pentane.

[0192] 

[0193] Using a procedure analogous to Example 2, 3'-[5-(3-oxo-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-hydroxy-3-methylphenyl]pentane gives the title compound (4.6 g, 98%).
¹NMR (300MHz, DMSO-d₆) δ ppm: 0.61 (t, J = 7.3 Hz, 6H), 0.78 (s, 9H), 1.35 (m, 1H), 1.57 (m, 1H), 1.87-2.11 (m, 4H), 2.04 (s, 3H), 2.06 (s, 3H), 2.58 (m, 1H), 2.96 (dd, J = 6.2, 9.1 Hz, 1H), 4.36 (d, J = 6.2 Hz, 1H), 6.51 (s, 1H), 6.65 (d, J = 8.1Hz, 1H), 6.85 (dd, J = 2.2, 8.4 Hz, 1H), 6.90 (s, 1H), 9.03 (s, 1H).
High Res. ES-MS: 389.2502; calc. for C₂₄H₃₆O₂S+H: 389.2514.

B.3'-[5-(3-Hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(methoxycarbonylmethoxy)-3-methylphenyl]pentane.

[0194] 

[0195] Using a procedure analogous to Example 1D, 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-hydroxy-3-methylphenyl]pentane is reacted with NaH and methyl chloroacetate to give the title compound (1.85 g, 92%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.78 (s, 9H), 1.35 (m, 1H), 1.58 (m, 1H), 1.92-2.02 (m, 4H); 2.04 (s, 3H), 2.14 (s, 3H), 2.55 (m, 1H), 2.78 (m, 1H), 2.95 (m, 1H), 3.69 (s, 3H), 4.38 (br s, 1H), 4.78 (s, 2H), 6.53 (s, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.98 (m, 2H).
High Res. ES-MS: 461.2738; calc. for C₂₇H₄₀O₄S+H: 461.2726.

Example 32

Preparation of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(carboxylmethoxy)-3-methytphenyl]pentane.

[0196] 

[0197] Using a procedure analogous to Example 3, 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]- 3'-[4-(methoxycarbonylmethoxy)-3-methylphenyl]pentane gives the title compound (1.4 g, 80%).
¹NMR (300MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.78 (s, 9H), 1.59 (m, 1H), 1.61 (m, 1H), 1.90-2.07 (m, 4H), 2.04 (s, 3H), 2.14 (s, 3H), 2.58 (m, 1H), 2.78 (m, 1H). 2.96 (m, 1H), 4.37 (d, J = 6.2 Hz, 1H), 4.64 (s, 2H), 6.53 (s, 1H), 6.68 (d, J = 9.1 Hz, 1H), 7.00 (m, 2H), 12.92 (br s, 1H).
High Res. ES-MS: 469.2392; calc. for C₂₆H₃₈O₄S+Na: 469.2389.

Example 33A & 33B

Preparation of enantiomers of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(carboxylmethoxy)-3-methylphenyl]pentane.

[0198] 

[0199] A racemic mixture of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(carboxylmethoxy)3-methylphenyl]pentane is chromatographed with a Chiralcel OJ column to give enantiomer 1, Example 33A (600 mg, 46%) and enantiomer 2, Example 33B (600 mg, 46%).
Enantiomer 1, Example 33A
HPLC: Chiralcel OJ (4.6X250 mm); 0.1% TFA in (2% MeOH and 5% EtOH in hept); 0.6 ml/m (flow rate); rt = 7.10 m; 240 nm.
¹NMR equivalent to Example 32.
High Res. ES-MS: 469.2393; calc. for C₂₆H₃₈O₄S+Na: 469.2389.
Enantiomer 2, Example 33B.
HPLC: Chiralcel OJ (4.6X250 mm); 0.1% TFA in (2% MeOH and 5% EtOH in hept); 0.6 ml/m (flow rate); rt =10.50 m; 240 nm.
¹NMR equivalent to Example 32.
High Res. ES-MS: 469.2385; calc. for C₂₆H₃₈O₄S+Na: 469.2389.

Example 34

Preparation of isomer 1 of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(tetrazol-5-yl-aminocarbonylmethoxy)-3-methylphenyl]pentane.

[0200] 

[0201] Using a procedure analogous to Example 24 and crystallization from Et2O/hex, enantiomer 1 of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(carboxylmethoxy)-3-methylphenyl]pentane (Example 33A) and 5-aminotetrazole give the title compound as a white solid (45 mg, 20%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.62 (t, J = 7.3 Hz, 6H), 0.77 (s, 9H), 1.33 (m, 1H), 1.57 (m, 1H), 1.92-2.00 (m, 4H), 2.04 (s, 3H), 2.19 (s, 3H), 2.56 (m, 1H), 2.78 (m, 1H), 2.95 (m, 1H), 4.38 (d, J = 6.3 Hz, 1H), 4.86 (s, 2H), 6.52 (s, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.99 (m, 2H), 12.21 (br s, 1H), 15.97 (br s, 1H).
High Res. ES-MS: 536.2677; calc. for C₂₇H₃₉O₃N₅S+Na: 536.2671.

Example 35

Preparation of isomer 2 of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]-3'-[4-(tetazol-5-yl-aminocarbornylmethoxy)-3-methylphenyl]pentane.

[0202] 

[0203] Using a procedure analogous to Example 24 with crystallization from Et₂O/hex, enantiomer 2 of 3'-[5-(3-hydroxy-4,4-dimethylpentyl)-4-methylthiophen-2-yl]3'-[4-(carboxylmethoxy)-3-methylphenyl]pentane (Example 33B) and 5-aminotetrazole give the title compound as a white solid (70 mg, 32%).
¹NMR equivalent to Example 34.
High Res. ES-MS: 536.2690; calc. for C₂₇H₃₉O₃N₅S+Na: 536.2671.

Add Preparation of racemic 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-(tetrazol-5-yl-aminocarbonyl)- 4-methylthiophen-2-yl]pentane.

Example 36

Preparation of isomer 1 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-(tetrazol-5-yl-aminocarbonyl)- 4-methylthiophen-2-yl]pentane.

[0204] 

[0205] Using a procedure analogous to Example 24 and crystallization from CH2Cl2, enantiomer 1 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)3-methylphenyl]-3'-[5-carboxyl-4-methylthiophen-2-yl]pentane (Example 7) and 5-aminotetrazole give the title compound as a white solid (335 mg, 77%).
¹NMR (300MHz, DMSO-d₆) δ ppm: 0.67 (t, J = 7.3 Hz, 6H), 0.93 (s, 9H), 2.00-2.15 (m, 4H), 2.13 (s, 3H), 2.46 (s, 3H), 3.46 (m, 1H), 3.77 (dd, J = 7.3, 9.9 Hz, 1H), 4.04 (dd, J = 2.9, 10.2 Hz, 1H), 4.80 (d, J = 5.5 Hz, 1H), 6.87 (m, 2H), 7.04 (m, 2H), 11.80 (s, 1H), 15.92 (br s, 1H).
High Res. ES-MS: 486.2556; calc. for C₂₅H₃₅O₃N₅S+H: 486.2539.

Example 37

Preparation of isomer 2 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-(tetrazol-5-yl-aminocarbonyl)- 4-methylthiophen-2-yl]pentane.

[0206] 

[0207] Using a procedure analogous to Example 24 and crystallization from CH2Cl2, enantiomer 2 of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-carboxyl-4-methylthiophen-2-yl]pentane (Example 8) and 5-aminotetrazole give the title compound as a white solid (335 mg, 77%).
¹NMR (300MHz, DMSO-d₆) δ ppm: 0.67 (t, J = 7.3 Hz, 6H), 0.93 (s, 9H), 2.00-2.15 (m, 4H), 2.13 (s, 3H), 2.46 (s, 3H), 3.46 (m, 1H), 3.77 (dd, J = 7.3, 9.9 Hz, 1H), 4.04 (dd, J = 2.9, 10.2 Hz, 1H), 4.80 (d, J = 5.1 Hz, 1H), 6.87 (m, 2H), 7.04 (m, 2H), 11.80 (s, 1H), 15.92 (br s, 1H).
High Res. ES-MS: 486.2545; calc. for C₂₅H₃₅O₃N₅S+H: 486.2539.

Example 38

Preparation of 5-[1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methylphenyl]propyl]-3-methylthiophene-2-carboxylic acid (2-methylsulfonyl-ethyl) amide.

[0208] 

[0209] To a mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (0.6344 g, 1.52 mmol) and CH₂Cl₂ (10 mL) is added Et₃N (0.85 mL, 6.07 mmol), followed by hydrochloride salt of 2-aminoethylmethylsulfone (0.2416 g, 1.52 mmol), EDCI (0.320 g, 1.67 mmol), and HOBT (0.226 g, 1.67 mmol). The resulting solution is stirred at RT overnight, diluted with CH₂Cl₂ (30 mL), washed with 1.0 M HCl (3 x 20 mL), brine (20 mL), dried over MgSO₄, and concentrated. The resulting residue is purified by chromatography (50% EtOAc/Hex) to give the titled compound (0.4042 g, 0.77 mmol, 51%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.3 Hz, 6H), 1.03 (s, 9H), 2.09 (q, J = 7.3 Hz, 4H), 2.21 (s, 3H), 2.42 (d, J = 3.0 Hz, 1H), 2.46 (s, 3H), 2.98 (s, 3H), 3.32 (t, J = 6.4 Hz, 2H), 3.71 (dt, J = 8.9, 2.9 Hz, 1H), 3.84-3.94 (m, 3H), 4.10 (dd, J = 9.3, 2.5 Hz, 1H), 6.44 (t, J = 5.8 Hz, 1H), 6.59 (s, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 1.7 Hz, 1H), 7.03 (dd, J = 8.7, 2.5 Hz, 1H). LC/MS (m/z): calcd for C₂₁H₄₂NO₅S₂ (M+H)⁺: 524.8; found: 524.2.

Example 39 and Example 40

Preparation of enantiomers of 5-[1-ethyl-1-[4-(2-hydroxy-3,3-dimetnyl-butoxy)-3-methylphenyl]propyl]-3-methylthiophene-2-carboxylic acid (2-methylsulfonyl-ethyl) amide.

[0210] 

[0211] A racemic mixture of 5-[1-ethyl-1-[4-(2-hydroxy-3,3-dimetnyl-butoxy)-3-methylphenyl]propyl]-3-methylthiophene-2-carboxylic acid (2-methylsulfonyl-ethyl) amide (247mg) is chromatographed (CHIRALPAK AD column, 40% i-PrOH/Hept) to give enantiomer 1, Example 39 (100 mg, 40 %) and enantiomer 2, Example 40 (80 mg, 32%).
Example 39, Enantiomer 1 :
rt=6.0m
NMR & LC/MS: Identical to the racemic material, Example 38.
Example 40, Enantiomer 2 :
rt = 10.2 m
NMR & LC/MS: Identical to the racemic material, Example 38.

Example 41

Preparation of 5-{1-[4-(3,3-Dimethyl-2-oxo-butyoxy)3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-carbolic acid (2-methanesulfonyl-ethyl]-amide.

[0212] 

[0213] To a solution of 5-[1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methylphenyl]propyl]-3-methylthiophene-2-carboxylic acid (2-methylsulfonyl-ethyl) amide, Example 38 (0.1096 g, 0.21 mmol) in CH₂Cl₂ (10 mL) is added NMO (37 mg, 0.31 mmol), and TPAP (3.7 mg, 0.01 mmol). The resulting solution is stirred at RT for 5 m, then it is filtered through a silica gel column, and washed with excess amount of EtOAc. Concentration of the solvent resulted in the title compound (62 mg, 0.12 mmol, 57%).
¹H NMR (EDCl₃), δ 0.70 (t, J = 8.0 Hz, 6H), 1.27 (s, 9H), 1.99 (m, 4H), 2.18 (s, 3H), 2.38 (s, 3H), 2.90 (s, 3H), 3.24 (t, J = 6.0 Hz, 2H), 3.82 (m, 2H), 6.36 (t, J = 5.8 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 6.85-6.95 (m, 2H).
LC/MS (m/z): 522.1 (M+H)⁺.

Example 42

Preparation of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propyl}-3methyl-thiophene-2-carboxylic acid methoxy-methyl-amide.

[0214] 

[0215] Using the procedure analogous to Example 38, from 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (0.34 g, 0.81 mmol) and N-methoxy-N-methylamine hydrochloride salt (0.087 g, 0.89 mmol) furnished the titled compound (0.2083 g, 0.45 mmol, 56%).
¹H NMR (CD₃OD), δ 0.65 (t, J= 7.4 Hz, 6H), 0.95 (s, 9H), 2.07 (q,J= 7.4 Hz, 4H), 2.14 (s, 3H), 2.35 (s, 3H), 3.25 (s, 3H), 3.57 (dd, J = 7.8, 2.9 Hz, 1H), 3.58 (s, 3H), 3.82 (dd, J = 9.7, 7.8 Hz, 1H), 4.07 (dd, J=9.7, 2.9 Hz, 1H), 6.62 (s, 1H), 6.73 (d, J = 8.9 Hz, 1 H), 6.94 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.9, 2.4 Hz,1H). LC/MS (m/z): calcd for C₂₆H₄₀NO₄S (M+H)⁺: 462.2; found: 462.2.

Example 43 and Example 44

Preparation of enantiomers of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propyl}-3methyl-thiophene-2-carboxylic acid methoxy-methyl-amide.

[0216] 

[0217] A racemic mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propyl}-3methyl-thiophene-2-carboxylic acid methoxy-methyl-amide (92 mg) is chromatographed (CHIRALPAK AD column, 40% i-PrOH/Hept) to give enantiomer 1, Example 43 (42 mg, 46 %) and enantiomer 2, Example 44 (34.5 mg, 38 %).
Example 43, Enantiomer 1 :
rt = 4.4 m
NMR & LC/MS: Identical to the racemic material, Example 42.
Example 44, Enantiomer 2 :
rt=7.3m
NMR & LC/MS: Identical to the racemic material, Example 42.

Example 45

Preparation of 5-{1-[4-(3,3-dimethyl-2-oxo-butyoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3methyl-thiophene-2-carboxylic acid methoxy-methyl-amide.

[0218] 

[0219] Using a procedure analogous to Example 41, from 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methoxy-methyl-amide (Example 42) (110 mg, 0.245 mmol) yielded the titled compound (107.9 mg, 98%).¹H NMR (CDCl₃), δ 0.71 (t, J= 6.4 Hz, 6H), 1.27 (s, 9H), 2.09 (q, J = 6.4 Hz, 4H), 2.27 (s, 3H), 2.48 (s, 3H), 3.30 (s, 3H), 3.67 (s, 3H), 4.85 (s, 2H), 6.52 (d,J= 8.6 Hz, 1H), 6.57 (s, 1H), 7.00 (d, J = 8.6 Hz, 1H), 7.02 (s,1H). LC/MS (m/z): calcd for C₂₆H₃₈NO₄S (M+H)⁺: 460.2; found: 460.2.

Example 46

Preparation of 2-[5-{1-Ethyl-1-{4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid methyl ester.

[0220] 

[0221] Using the procedure analogous to Example 38, from 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (0.4307 g, 1.03 mmol) and glycine methyl ester hydrochloride (0.129 g, 1.03 mmol) furnished the titled compound (0.2535 g, 50%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 6.8 Hz, 6H), 1.03 (s, 9H), 2.09 (q,J= 6.8 Hz, 4H), 2.21 (s, 3H), 2.44 (d, J = 2.5 Hz, 1H), 2.48 (s, 3H), 3.72 (dt, J = 8.3, 2.5 Hz, 1H), 3.78 (s, 3H), 3.87 (t, J = 8.8 Hz, 1H), 4.11 (dd, J = 9.2, 2.5 Hz, 1H), 4.17 (d, J = 5.4 Hz, 2H), 6.20 (s, 1H), 6.61 (s, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.99-7.01 (m, 1H), 7.04 (dd, J = 8.8, 2.4 Hz, 1H).
LC/MS (m/z): 490.2 (M+H)⁺.

Example 47

Preparation of 2-[5-{1-Ethyl-1-{4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid.

[0222] 

[0223] 2-[5-{1-Ethyl-1-{4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid methyl ester (Example 46) (0.24 g, 0.49 mmol) is dissolved in THF (5 mL), treated with H₂O (1 mL) and LiOH (59 mg, 2.46 mmol) and the resulting mixture is stirred at RT overnight. The solution is diluted with H₂O (10 mL), the pH value is adjusted to ca. 3-4 using 1M HCl, it is extracted with EtOAc (2 x 40 mL), dried with MgSO₄, filtered and concentrated to yield the titled compound (0.233 g, 0.49 mmol, 99%). ¹H NMR (CD₃OD), δ 0.75 (t, J = 7.4 Hz, 6H), 1.05 (s, 9H), 2.17 (q, J = 7.4 Hz, 4H), 2.23 (s, 3H), 2.48 (s, 3H), 3.66 (dd, J = 7.8 2.9 Hz, 1H), 3.91 (dd, J = 9.6, 7.8 Hz, 1H), 4.01 (s, 2H), 4.16 (dd, J = 9.6, 2.9 Hz, 1H), 6.74 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 7.03-7.06 (m, 1H), 7.11 (dd, J = 8.2, 2.5 Hz, 1H). LC/MS (m/z): calcd for C₂₆H₃₈NO₅S
(M+H)⁺: 476.2; found: 476.2.

Example 48 and Example 49

Preparation of enantiomers of 2-[5-{1-Ethyl-1-{4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid.

[0224] 

[0225] A racemic mixture of 2-[5-{1-Ethyl-1-{4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenyl-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid, Example 47 (130 mg) is chromatographed (CHIRALPAK AD column, 20% i-PrOH/Hept, 0.2%TFA) to give enantiomer 1, Example 48 (47.9 mg, 37%) and enantiomer 2, Example 49 (39 mg, 30%).

Example 48, Enantiomer 1:

[0226] rt = 6.5 m
NMR & LC/MS: Identical to the racemic material, Example 47.

Example 49, Enantiomer 2 :

[0227] rt=15.2 m
NMR & LC/MS: Identical to the racemic material, Example 47.

Example 50

Preparation of 2-[5-{1-[4-(3,3-Dimethyl-2-oxo-butyoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid.

[0228] 

[0229] 2-[5-{1-Ethyl-1-{4-(2-hydroxy-3,3-dimethyl-butyoxy)-3-methyl-phenylpropyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid (Example 47) (99 mg, 0.21 mmol) is dissolved in CH₂Cl₂ (4 mL), treated with Dess-Martin reagent (97 mg, 0.23 mmol). The resulting mixture is stirred at RT 2h. It is diluted with EtOAc (25 mL), washed with 10% Na₂SO₃ (2 x 20 mL) along with 0.1 M HCl (20 mL); dried with MgSO₄, filtered and concentrated. Purification of the resulting crude product by flash chromatography, eluted with 15% CH₃OH/EtOAc with 0.5%HOAc yielded the titled compound (56.2 mg, 0.11 mmol, 53%). ¹H NMR (CD₃OD), δ 0.75 (t, J = 7.2 Hz, 6H),1.29 (s, 9H), 2.19 (q, J = 7.2 Hz, 4H), 2.25 (s, 3H), 2.47 (s, 3H), 4.02 (s, 2H), 5.05 (s, 2H), 6.66 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 7.00-7.11 (m, 2H), 7.96 (bs, 1H).
LC/MS (m/z): calcd for C₂₆H₃₆NO₅S (M+H)⁺: 474.2; found: 474.2.

Example 51

Preparation of (5-{1-ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid.

[0230] 

A. 2-{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-acetic acid methyl ester.

[0231] 

[0232] 4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenol (10.66g, 38.9 mmol) is reacted with methyl bromoacetate (4.4 ml, 46.7 mmol) and K₂CO₃ (10.70 g, 77.81 mmol), in acetone (100 m) at refluxing temperature overnight. The reaction is cooled to RT, filtered and washed with Et₂O and concentrated. The crude product is purified by chromatography to give the titled compound (12.15 g, 35.1 mmol, 90%).
¹H NMR (CD₃Cl₃), δ 0.70 (t, J = 7.2 Hz, 6H), 2.04-2.12 (m, 4H), 2.21 (s, 3H), 2.26 (s, 3H), 3.81 (s, 3H), 4.63 (s, 2H), 6.57-6.61 (m, 2H), 6.69-6.71 (m, 1H), 7.02-7.06 (m, 2H). LC/MS (m/z): calcd for C₂₀H₂₇O₃S (M+H)⁺: 347.5; found: 347.1.

B. 3-{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxymethyl}-pentan-3-ol.

[0233] 

[0234] {4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}acetic acid methyl ester (5.52 g, 15.95 mmol) is dissolved in THF (50 mL). The solution is cooled to 0 °C, and treated with Ethyl magnesiumbromide (3.0 M, 13.3 mL) in a dropwise fashion. The reaction is stirred at 0 °C for 10 m, and refluxed for 3 h. It is cooled to 0 °C, quenched with sat. NH₄Cl (50 mL), then 1.0 M HCl (30 mL) is added. It is extracted with EtOAc (2 x 100 mL), dried and concentrated. The crude product is purified by chromatography to give the titled compound (5.22 g, 13.96 mmol, 87%).
¹H NMR (CD₃Cl₃), δ 0.71 (t, J = 7.4 Hz, 6H), 0.95 (t, J = 7.1 Hz, 6H), 1.62-1.73 (m, 4H), 2.04-2.14 (m, 4H), 2.21 (s, 6H), 3.81 (s, 2H), 6.59-6.61 (m, 1H), 6.69-6.74 (m, 2H), 7.02-7.08 (m, 2H). LC/MS (m/z): calcd for C₂₃H₃₅O₂S (M+H)⁺: 375.6; found: 375.3.

C. 5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester.

[0235] 

[0236] 3-{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxymethyl}-pentan-3-ol, Example 51B (0.50g, 1.34 mmol) is dissolved in THF (10 mL). The solution is cooled to 0 °C, treated with nBuLi (1.6 M, 1.8 mL, 2.95 mmol). It is stirred at 0°C for 20 min, and methyl chloroformate (113 µL, 1.47 mmol) is added. The reaction is stirred at 0 °C for 10 min and RT for 20 m before it is quenched with satd NH₄Cl (5 mL). It is diluted with H₂O (10 mL), treated with 0.1 M HCl (10 ml) and extracted with EtOAc (3 x 15 mL), dried and concentrated. The crude product is purified by chromatography to give the titled compound (0.24 g, 0.56 mmol, 41%).
¹H NMR (CD₃Cl₃), δ 0.71 (t, J = 7.1 Hz, 6H), 0.95 (t, J = 7.9 Hz, 6H), 1.64-1.72 (m, 4H), 2.11 (q, J = 7.1 Hz, 4H), 2.21 (s, 3H), 2.49 (s, 3H), 3.81 (s, 3H), 6.61 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.85-7.01 (m, 2H). LC/MS (m/z): calcd for C₂₅H₄₀NO₄S (M+NH₄)⁺: 450.3; found: 450.3.

D. 5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid.

[0237] 

[0238] Using a procedure analogous to Example 47,5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester (0.23 g, 0.53 mmol) gives the title compound (0.20 g, 0.48 mmol, 91 %).
¹H NMR (CD₃Cl₃), δ 0.72 (t, J = 7.6 Hz, 6H), 0.95 (t, J = 7.1 Hz, 6H), 1.64-1.72 (m, 4H), 2.11 (q, J = 7.6 Hz, 4H), 2.22 (s, 3H), 2.49 (s, 3H), 3.82 (s, 3H), 6.62 (s, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.99-7.06 (m, 2H). LC/MS (m/z): calcd for C₂₄H₃₃O₄S
(M-H)⁺: 417.6; found: 417.2.

Example 52

Preparation of 2-[(5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid methyl ester.

[0239] 

[0240] Using a procedure analogous to Example 38,5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 51) (0.3 g, 0.72 mmol), glycine methyl ester hydrochloride, and DMF (2 mL) as reaction solvent to give the title compound (0.34 g, 0.69 mmol, 97%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.1 Hz, 6H), 0.95 (t, J = 7.1 Hz, 6H), 1.63-1.72 (m, 4H), 2.04-2.14 (m, 4H), 2.21 (s, 3H), 2.48 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 4.15 (d, J = 5.2 Hz, 2H), 6.20 (t, J = 5.2 Hz, 1H), 6.63 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.98-7.01 (m, 1H), 7.01-7.06 (m, 1H). LC/MS m/z): calcd. for C₂₇H₃₈NO₅S (M-H)^-: 488.7; found: 488.5.

Example 53

Preparation of 2-[(5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid.

[0241] 

[0242] 2-[(5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid methyl ester (Example 52) (0.34 g, 0.69 mmol) is dissolved in MeOH (2 mL), treated with H₂O (0.5 mL) and NaOH (0.14 g, 3.47 mmol) and the resulting mixture is heated at a reflux for two hours cooled to at ambient temperature and stirred overnight. The solution is diluted with H₂O (10 mL), the pH value is adjusted to about 3-4 using 1 M HCl, it is extracted with EtOAc (40 mL). The EtOAc layer is washed with brine (20 mL), dried with MgSO₄, filtered and concentrated to yield the titled compound (0.244 g, 0.51 mmol, 74%). ¹H NMR (CD₃OD), δ 0.72 (t, J = 7.4 Hz, 6H), 0.94 (t, J = 7.4 Hz, 6H), 1.64-1.74 (m, 4H), 2.03-2.20 (m, 4H), 2.18 (s, 3H), 2.44 (s, 3H), 3.79 (s, 2H), 3.97-3.99 (m, 2H), 6.71 (s, 1H), 6.79 (d, J = 8.2 Hz, 1H), 6.99-7.02 (m, 1H), 7.06-7.10 (m, 1H), 7.88-7.94 (t, J = 5.7 Hz, 1H). LC/MS (m/z): calcd. for C₂₆H₃₆NO₅S (M-H)^-: 475.6; found: 474.3

Example 54

Preparation of epimer 2 of L-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)amino]propionic acid methyl ester.

[0243] 

[0244] Using a procedure analogous to Example 52, enantiomer 2 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 8) (0.50 g, 1.2 mmol) and L-alanine methyl ester hydrochloride salt (0.18 g, 1.3 mmol) to give the titled compound (0.44 g, 0.87 mmol, 73%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.2 Hz, 6H), 1.02 (s, 9H), 1.47 (d, J = 7.2 Hz, 3H), 2.04-2.14 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 3.71 (dd, J = 8.6, 2.5 Hz, 1H), 3.77 (s, 3H), 3.88 (t, J = 8.6 Hz, 1H), 4.10 (dd, J = 9.2, 2.5 Hz, 1H), 4.67-4.75 (m, 1H), 6.26 (d, J = 7.1 Hz, 1H), 6.60 (s, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.97-7.06 (m, 2H). LC/MS (m/z): calcd. for C₂₈H₄₂NO₅S (M+H)⁺: 504.7; found: 504.4.

Example 55

Preparation of epimer 2 of L-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-propionic acid.

[0245] 

[0246] Using a procedure analogous to Example 53, epimer 2 of L-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-propionic acid methyl ester (0.42g, 1.0mmol) gives the title compound (0.37 g, 0.76 mmol, 73%). ¹HNMR (CDCl₃), δ 0.71 (t, J = 7.4 Hz, 6H), 1.02 (s, 9H), 1.51 (d, J = 7.7 Hz, 3H), 2.04-2.14 (m, 4H), 2.20 (s, 3H), 2.47 (s, 3H), 3.72 (dd, J = 8.7, 2.5 Hz, 1H), 3.87 (t, J = 8.7, 1H), 4.10 (dd, J = 9.3, 2.8 Hz, 1 H), 4.64-4.72 (m, 1H), 6.22 (d, J = 7.4, 1H), 6.62 (s, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.97-7.06 (m, 2H). LC/MS (m/z): calcd. for C₂₇H₄₀NO₅S (M+H)⁺: 490.7; found: 490.4.

Example 56

Preparation of epimer 2 of D-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-propionic acid methyl ester.

[0247] 

[0248] Using a procedure analogous to Example 52, enantiomer 2 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 8) (0.40 g, 0.96 mmol) and D-alanine methyl ester hydrochloride salt (0.15 g, 1.05 mmol) to give the title compound (0.48 g, 0.95 mmol, 71%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.5 Hz, 6H), 1.02 (s, 9H), 1.47 (d, J = 7.0 Hz, 3H), 2.04-2.15 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 3.71 (d, J = 8.6 Hz, 1H), 3.77 (s, 3H), 3.87 (t, J = 9.2, 1 H) 4.10 (dd, J = 9.1, 2.7 Hz, 1H), 4.66-4.76 (m, 1H), 6.26 (d, J = 7.6, 1H), 6.60 (s, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.98-7.07 (m, 2H). LC/MS (m/z): calcd. for C₂₈H₄₂NO₅S (M+H)⁺: 504.7; found: 504.4.

Example 57

Preparation of epimer 2 of D-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-propionic acid.

[0249] 

[0250] Using a procedure analogous to Example 53, epimer 2 of D-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-propionic acid methyl ester (0.34g, 0.68 mmol) gives the title compound (0.33 g, 0.66 mmol, 79%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.5 Hz, 6H), 1.02 (s, 9H), 1.52 (d, J = 7.1 Hz, 3H), 2.04-2.14 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 3.71 (dd, J = 8.8, 2.7 Hz, 1 H), 3.88 (t, J= 8.8, 1H), 4.10 (dd, J = 9.2, 2.7 Hz, 1H), 4.64-4.73 (m, 1H), 6.21 (d, J = 6.9, 1H), 6.62 (s, 1H), 6.73 (d, J = 8.6 Hz, 1H), 6.98-7.06.(m, 2H). LC/MS (m/z): calcd. for C₂₇H₄₀NO₅S (M+H)⁺: 490.7; found: 490.2.

Example 58

Preparation of L-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-succinic acid dimethyl ester.

[0251] 

[0252] Using a procedure analogous to Example 52, enantiomer 2 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 8) (0.4 g, 0.96 mmol) and L-aspartic acid dimethyl ester hydrochloride salt (0.21 g, 1.05 mmol) to give the title compound (0.42 g, 0.758 mmol, 78%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.7 Hz, 6H), 1.02 (s, 9H), 2.04-2.14 (m, 4H), 2.20 (s, 3H), 2.47 (s, 3H), 2.93 (dd, J = 17.2, 4.5 Hz, 1H), 3.10 (dd, J = 17.2, 4.3 Hz, 1H), 3.69-3.73 (m, 4H), 3.78 (s, 3H), 3.87 (t, J = 9.1, 1 H), 4.10 (dd, J = 9.1, 2.6, 1H), 4.96-5.01 (m, 1H), 6.58 (s, 1H), 6.72 (d, J = 7.7, 1H), 6.78 (d, J = 7.8, 1H), 7.00 (d, J = 1.7, 1H), 7.04 (dd, J = 2.7, 8.5, 1H) . LC/MS (m/z): calcd. for C₃₀H₄₄NO₇S (M+H)⁺: 562.7; found: 562.4.

Example 60

Preparation of epimer 2 of D-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-succinic acid dimethyl ester.

[0253] 

[0254] Using a procedure analogous to Example 52, enantiomer 2 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 8) (0.4 g, 0.96 mmol) and D-aspartic acid dimethyl ester hydrochloride salt (0.21 g, 1.05 mmol) to give the title compound (0.42 g, 0.75 mmol, 78%).¹H NMR (CDCl₃), δ 0.71 (t, J = 7.4 Hz, 6H), 1.02 (s, 9H), 2.04-2.14 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 2.94 (dd, J =17.0, 4.6 Hz, 1 H), 3.10 (dd, J = 17.0, 4.6 Hz, 1H), 3.69-3.74 (m, 4H), 3.78 (s, 3H), 3.87 (t,J= 9.1 Hz, 1H), 4.10 (dd, J= 9.1, 3.0 Hz, 1H), 4.96-5.02 (m, 1 H), 6.59 (s, 1 H), 6.73 (d, J = 8.4 Hz; 1H), 6.78'(d, J = 7.2 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 2.7, 8.4 Hz, 1H) . LC/MS (m/z): calcd. for C₃₀H₄₄NO₇S (M+H)⁺: 562.7; found: 562.4.

Example 62:

Preparation of epimer 2 of L-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-3-hydroxy-propionic acid methyl ester.

[0255] 

[0256] Using a procedure analogous to Example 52, enantiomer 2 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 8) (0.4 g, 0.96 mmol) and L-serine methyl ester hydrochloride salt (0.16 g, 1.05 mmol) to give the title compound (0.41 g, 0.79 mmol, 82%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.7 Hz, 6H), 1.02 (s, 9H), 2.04-2.14 (m, 4H), 2.21 (s, 3H), 2.49 (s, 3 H), 3.71 (dd, J = 8.6, 2.6 Hz, 2H), 3.81 (s, 3H), 3.87 (t, J = 8.7 Hz, 1H), 4.01 (d, J = 3.5 Hz, 2H), 4.09 (dd, J = 5.0, 2.7 Hz, 1H), 4.77-4.81 (m, 1H), 6.61 (s, 1H), 6.65 (d, J = 6.6 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.99 (d, J =1.8Hz, 1H), 7.04 (dd, J = 8.9, 2.6 Hz, 1H). LC/MS (m/z): calcd. for C₂₈H₄₂NO₆S (M+H)⁺: 520.7; found: 520.2.

Example 64:

Preparation of epimer 1 of L-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-propionic acid methyl ester.

[0257] 

[0258] Using a procedure analogous to Example 52, enantiomer 1 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 1) (0.50 g,1.19 mmol) and L-alanine methyl ester hydrochloride salt (0.18 g, 1.31 mmol) to give the title compound (0.3 g, 0.60 mmol, 50%). ¹H-NMR and LC/MS: identical to (D-epimer-2), Example 56.

Example 65:

Preparation ofepimer 1 of L-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-propionic acid.

[0259] 

[0260] Using a procedure analogous to 53, epimer 1 of L-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-propionic acid methyl ester (0.3g, 0.60 mmol) gives the title compound (0.27 g, 0.55 mmol, 93%). ¹H NMR and LC/MS: identical to (D-epimer-2), Example 57.

Example 66

Preparation ofepimer 1 of D-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-propionic acid methyl ester.

[0261] 

[0262] Using a procedure analogous to Example 52, enantiomer 1 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 7) (0.5 g, 1.19 mmol) and D-alanine methyl ester hydrochloride salt (0.18 g, 1.31 mmol) to give the title compound (0.4 g, 0.79 mmol, 66%). ¹H NMR and LC/MS: identical to 2133006 (L-Epimer-2), Example 54.

Example 69

[0263] Preparation of epimer 1 of L-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-3-methyl-pentanoic acid.

[0264] Using a procedure analogous to Example 53, epimer 1 of L-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-3-methyl-pentanoic acid methyl ester (0.2g, 0.37 mmol) gives the title compound (0.16 g, 0.30 mmol, 84%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.5 Hz, 6H), 0.94-1.02 (m, 6H), 1.03 (s, 9H), 1.21-1.32 (m, 1H), 1.48-1.62 (m, 1H), 1.98-2.16 (m, 5H), 2.21 (s, 3H), 2.47 (s, 3H), 3.72 (dd, J = 8.5, 2.6 Hz, 1H), 3.88 (t, J = 8.5 Hz, 1H), 4.10 (dd, J = 9.3, 2.7 Hz, 1H), 4.73 (dd, J = 7.8, 4.8 Hz, 1H), 6.18 (d, J = 8.7, 1H), 6.60 (s, 1H), 6.73 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.4,2.2 Hz, 1H). LC/MS (m/z): calcd. for C₃₀H₄₆NO₅S (M+H)⁺: 531.8; found: 532.1.

Example 70

Preparation of enantiomer 1 of 2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.

[0265] 

[0266] Using the procedure analogous to Example 52, enantiomer 1 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 7) (0.2 g, 0.48 mmol) and 2-amino-2-methyl-propionic acid methyl ester hydrochloride salt (0.018 g, 0.53 mmol) to give the title compound (0.20 g, 0.39 mmol, 71%). ¹H NMR (CDCl₃), δ 0.69 (t, J = 7.0 Hz, 6H), 1.01 (s, 9H), 1.60 (s, 6H), 2.02-2.13 (m, 4H), 2.19 (s, 3H), 2.44 (s, 3H), 3.70 (dd, J= 8.9, 2.6 Hz, 1 H), 3.76 (s, 3H), 3.86 (t, J = 8.7, 1H), 4.09 (dd, J = 9.4, 2.6 Hz, 1H), 6.28 (s, 1H), 6.59 (s, 1H), 6.73 (d, J = 8.4 Hz, 1 H), 6.99 (d, J = 2.2 Hz,1H), 7.04 (dd, J= 8.4, 2.2 Hz, 1H). LC/MS (m/z): calcd. for C₂₉H₄₄NO₅S (M+H)⁺: 518.7; found: 518.2.

Example 71

Preparation of enantiomer 1 of 2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-2-methyl-propionic acid.

[0267] 

[0268] Using a procedure analogous to Example 53, enantiomer 1 of 2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester (0.20 g, 0.39 mmol) gives the title compound (0.17 g, 0.34 mmol, 84%). ¹H NMR (CDCl₃), δ 0.71 (t, J= 7.5 Hz, 6H), 1.02 (s, 9H), 1.65 (s, 6H), 2.03-2.14 (m, 4H), 2.21 (s, 3H), 2.47. (s, 3H), 3.71 (dd, J = 8.6, 2.5 Hz, 1H), 3.87 (t, J = 8.6, 1 H), 4.09 (dd, J = 9.2, 2.5 Hz, 1H), 6.11 (s, 1H), 6.63 (s, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.73 (d,J=8.4 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H-), 7.04 (dd, J = 8.4, 2.2 Hz, 1H). LC/MS (m/z): calcd. for C₂₈H₄₂NO₅S (M+H)⁺: 504.7; found: 504.2.

Example 72

Preparation of epimer 1 of L-1-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)pyrrolidine-2-carboxylic acid methyl ester.

[0269] 

[0270] Using a procedure analogous to Example 52, enantiomer 1 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 7) (0.20 g, 0.4778 mmol) and L-proline methyl ester hydrochloride salt (0.09 g, 0.53 mmol) to give the title compound (0.14 g, 0.26 mmol, 56%). ¹H NMR (CDCl₃), δ 0.69 (t, J = 7.4 Hz, 3H), 0.70 (t, J = 7.1 Hz, 3H), 1.00 (s, 9H), 1.85-2.14 (m, 7H), 2.19 (s, 3H), 2.21-2.36 (m, 4H), 3.60-3.78 (m, 6H), 3.86 (t, J = 9.3, 1H), 4.09 (dd, J = 9.3, 2.8 Hz, 1H), , 4.53-4.65 (m,1H), 6.53 (s, 1H), 6.71 (d, J = 8.9 Hz, 1H), 6.96-7.06 (m, 2H). LC/MS (m/z): calcd. for C₃₀H₄₄NO₅S (M+H)⁺: 530.8; found: 530.2.

Example 74

Preparation of epimer 2 of L-1-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester.

[0271] 

[0272] Using the procedure analogous to Example 52, enantiomer 2 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 8) (0.50 g, 1.19 mmol) and L-proline methyl ester hydrochloride salt (0.22 g, 1.3 mmol) to give the title compound (0.31 g, 0.59 mmol, 49%). ¹H NMR (CDCl₃), δ 0.70 (t, J = 7.1 Hz, 3H), 0.71 (t, J = 7.5 Hz, 1H), 1.02 (s, 9H), 1.87-2.15 (m, 7H), 2.20 (s, 3H), 2.22-2.38 (m, 4H), 3.60-3.78 (m, 6H), 3.87 (t, J = 9.3, 1H), 4.09 (dd, J = 9.3, 2.7 Hz, 1H), 4.53-4.65 (m, 1 H), 6.54 (s, 1H), 6.71 (d, J = 8.9 Hz, 1H), 6.96-7.06 (m, 2H). LC/MS (m/z): calcd. for C₃₀H₄₄NO₅S (M+H)⁺: 530.8; found: 530.2.

Example 75

Preparation of epimer 2 of L-1-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-pyrrolidine-2-carboxylic acid.

[0273] 

[0274] Using the procedure analogous to Example 53, epimer 2 of 2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester, (0.31 g, 0.59 mmol) gives the title compound (0.29 g, 0.56 mmol, 97%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.5 Hz, 6H), 1.02 (s, 9H), 1.92-2.15 (m, 8H), 2.20 (s, 3H), 2.36 (s, 3H), 2.41 (bs, 1H), 3.63-3.76 (m, 3H), 3.90 (t, J = 8.9, 1H), 4.10 (dd, J = 8.9, 2.5 Hz, 1H), 4.68-4.75 (m, 1H), 6.60 (s, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 7.03 (dd, J = 8.5, 2.3 Hz, 1H). LC/MS (m/z): calcd. for C₂₉H₄₂NO₅S (M+H)⁺: 516.7; found: 516.3.

Example 76

Preparation of enantiomer 2 of 2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.

[0275] 

[0276] Using the procedure analogous to Example 52, enantiomer 2 of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 8) (0.5 g, 1.19 mmol) and 2-amino-2-methyl-propionic acid methyl ester hydrochloride salt (0.2 g, 1.31 mmol) to give the title compound (0.44 g, 0.85 mmol, 71%). ¹H NMR and LC/MS: identical to (enantiomer-1), Example 70.

Example 77

Preparation of enantiomer of 2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-2-methyl-propionic acid.

[0277] 

[0278] Using the procedure analogous to Example 53, enantiomer 2 of 2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl).amino]-2-methyl-propionic acid methyl ester (0.44g, 0.85 mmol) gives the title compound (0.35 g, 0.69 mmol, 81%). ¹H NMR and LC/MS: identical to (enantiomer-1), Example 71.

Example 78

Preparation of D-1-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methylphenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester

[0279] 

[0280] Using a procedure analogous to Example 52, a racemic mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (0.6 g, 1.39 mmol) and D-proline methyl ester hydrochloride salt (0.28 g, 1.53 mmol) give the title compound (0.54 g, 1.02 mmol, 73%). ¹H NMR (CDCl₃), δ 0.70 (t, J = 7.1 Hz, 3H), 0.71 (t, J= 7.5 Hz, 3H) 1.02 (s, 9H), 1.88-2.16 (m, 7H), 2.20 (s, 3H), 2.22-2.38 (m, 4H), 3.61-3.79 (m, 6H), 3.87 (t, J = 8.8, 1H), 4.09 (dd, J = 9.1, 2.6 Hz, 1H), 4.56-4.65 (m, 1H), 6.54 (s, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.98-7.06 (m, 2H). LC/MS (m/z): calcd. for C₃₀H₄₄NO₅S (M+H)⁺: 530.8; found: 530.2.

Example 79 and 80

Preparation of epimers of D-1-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester.

[0281] 

[0282] A racemic mixture of D-1-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester (0.54 g) is chromatographed (CHIRALPAK AD column, 40% i-PrOH/Hept) to give epimer1, Example 79 ( 0.244 g, 45 %) and epimer 2, Example 80 ( 0.283 g, 52%).

Example 79, Epimer1 rt = 10.2 m

[0283] NMR & LC/MS: identical to 2158904 (L-epimer-2), Example 78.

Example 80, Epimer 2 rt = 18.1 m

[0284] NMR & LC/MS: identical to (L-epimer-1), Example 78.

Example 81

Preparation of Epimer 1 of D-1-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-pyrrolidine-2-carboxylic acid.

[0285] 

[0286] Using the procedure analogous to Example 53, epimer 1 of D-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester (Example 79) (0.24g, 0.46 mmol) gives the title compound (0.15 g, 0.29 mmol, 63%). ¹H NMR and LCTMS: identical to (L-enantiomer-2), Example 75.

Example 82

Preparation of epimer 2 of D-1-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-pyrrolidine-2-carboxylic acid.

[0287] 

[0288] Using a procedure analogous to Example 53, epimer-2 of D-1-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-pyrrolidine-2-carboxylic acid methyl ester (Example 80) (0.28 g, 0.53 mmol) gives the title compound (0.22 g, 0.43 mmol, 79%). ¹H NMR and LC/MS: identical to (L-epimer-1); Example 73.

Example 83

Preparation of D-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-3-methyl-butyric acid methyl ester

[0289] 

[0290] Using a procedure analogous to Example 52, a racemic mixture of 5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (Example 3) (0.60 g, 1.39 mmol) and D-valine methyl ester hydrochloride salt (0.29 g, 1.53 mmol) to give the title compound (0.54 g, 1.02mmol, 73%). LC/MS (m/z): calcd. for C₃₀H₄₆NO₅S (M+H)⁺: 532.8; found: 532.2.

Example 84 and 85

Preparation of epimers of D-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-3-methyl-butyric acid methyl ester.

[0291] 

[0292] A racemic mixture of D-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-3-methyl-butyric acid methyl ester (Example 83) (0.54 g) is chromatographed (CHIRALPAK AD column, 40% i-PrOH/Hept) to give epimer 1, Example 84 (0.36 g, 48 %) and epimer 2, Example 85 ( 0.33 g, 45%).
Example 84, Epimer 1
rt = 6.8 m ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.2 Hz, 6H), 0.96 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 7.1 H, 3H), 1.02 (s, 9H), 2.04-2.15 (m, 4H), 2.18 (s, 3H), 2.20-2.21 (m, 2H), 2.47 (s, 3H), 3.71 (dd, J = 8.8, 2.6 Hz, 1H), 3.76 (s, 3H), 3.88 (t, J = 8.8 Hz, 1H), 4.11 (dd, J = 9.2, 2.6 Hz, 1H), 4.69 (dd, J= 8.4, 4.9 Hz, 1 H), 6.19 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), 6.73 (d, J = 8.3 Hz, 1 H), 6.90-7.06 (m, 2H). LC/MS (m/z): calcd. for C₃₀H₄₆NO₅S
(M+H)⁺: 532.8; found: 532.2.
Example 85, Epimer 2
rt = 10.6 m
¹H NMR and LC/MS: identical to (D-enantiomer-1), example 33.

Example 86:

Preparation of epimer 1 of D-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-3-methyl-butyric acid

[0293] 

[0294] Using the procedure analogous to Example 53, epimer 1 of D-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester (Example 84) (0.28g, 0.53 mmol) gives the title compound (0.22 g, 0.43 mmol, 79%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.4 Hz, 6H), 1.00 (d, J = 6.6 Hz, 3H), 1.03 (s. 9H),1.04 (d, J = 6.6 Hz, 3H), 2.04-2.14 (m, 4H), 2.21 (s, 3H), 2.25-2.35 (m, 1H), 2.47 (s, 3H), 3.72 (dd, J = 8.4, 2.6 Hz, 1H), 3.88 (t, J = 9.2 Hz, 1H), 4.10 (dd, J = 9.2, 2.6 Hz, 1H), 4.69 (dd, J = 8.0, 4.4 Hz, 1 H), 6.19 (d, J = 8.0 Hz), 6.60 (s, 1H), 6.73 (d, J = 8.4 Hz, 1H), 7.00 (dd, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.4, 2.6 Hz, 1H). LC/MS (m/z): calcd. for C₂₉H₄₄NO₅S (M+H)⁺: 518.7; found: 518.2.

Example 87

Preparation of epimer 2 of D-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-3-methyl-butyric acid.

[0295] 

[0296] Using a procedure analogous to Example 53, epimer 2 of D-2-[(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl)-3-methyl-thiophene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester (Example 85) (0.33g, 0.62 mmol) gives the title compound (0.23 g, 0.44 mmol, 79%). ¹H NMR and LC/MS: equivalent to (D-epimer-1), Example 86.

Example 88

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0297] 

[0298] Using a procedure analogous to Example 3,3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (0.23 g, 0.55 mmol) and 5N sodium hydroxide (220 ul, 1.1 mmol) give the title compound (0.18 g, 81%).
H-NMR (ppm, CDCl₃): 7.68 (1H, d, 4.0 Hz), 7.03 (1H, d, 8.2 Hz), 6.98 (1H, s), 6.79 (1H, d, 4.0 Hz), 6.72 (1H, d, 8.2 Hz), 4.09 (1H, d, 9.3 Hz), 3.85 (1H, t, 9.3 Hz), 3.73 (1H, d, 9.3 Hz), 2.19 (3H, s), 2.13 (4H, q, 7.0 Hz), 1.02 (9H, s), 0.71 (6H, t, 7.0 Hz).
ES/MS: 403.2 (M+1) 422.2 (M + NH4).

Example 89 and 90

Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0299] 

[0300] A mixture of racemic 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-(5-carboxy-thiophen-2-yl]pentane (166 mg) is chromatographed with a ChiralPak AD column (10% IPA/hept to 15% IPA/hept) to give enantiomer 1 (63 mg), Example 89 and enantiomer 2 (67 mg), Example 90.
Enantiomer 1, Example 89
HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/85% heptane; 1 ml/m (flow rate); rt = 4.9 m; 225 nm.
Enantiomer 2, Example 90
HPLC: ChiralPak AD (4.6X250 mm); 15% EPA/85% heptane; 1 ml/m (flow rate); rt = 6.9 m; 225 nm.

Example 91

Preparation of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-(1-methylethyl)phenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0301] 

A. 3'-[4-(Hydroxy)-3-(1-methylethyl)phenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane.

[0302] 

[0303] Methyl, 5-(E/Z-2-penten-3-yl)thiophene-2-carboxylate (Example 5C) (0.21 g, 1.0 mmol), o-isopropylphenol (1.09 g, 4.0 mmol), and BF3-etherate (58 mg, 0.2 mmol) are reacted and purified as described in Example 5D to give the title compound (0.28 g, 81%).
H-NMR (ppm, CDCl₃): 7.62 (1H, d, 4.0 Hz), 7.05 (1H, s), 6.90 (1H, d, 8.8 Hz), 6.78 (1H, d, 4.0 Hz), 6.63 (1H, d, 8.8 Hz), 4.58 (1H, s), 3.83 (3H, s), 3.15 (1H, m), 2.11 (4H, q, 7.2 Hz), 1.21 (6H, d, 6.8 Hz), 0.71 (6H, t, 7.4 Hz).
ES/MS: 347.2 (M+1).

B. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-(1-methylethyl)phenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0304] 

[0305] 3'-[4-(Hydroxy)-3-(1-methylethyl)phenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane (0.18 g, 0.52 mmol), sodium hydride 60% (23 mg, 0.56 mmol), and 1-chloropinacolone (71 mg, 0.52 mmol) with a catalytic amount of potassium iodide (7 mg, 0.04 mmol) are reacted and purified as described in Example 5E to give the title compound (0.13 g, 56%).
H-NMR (ppm, CDCl₃): 7.61 (1H, d, 4.0 Hz), 7.08 (1H, s), 6.93 (1H, d, 6.0 Hz), 6.77 (1H, d, 4.0 Hz), 6.52 (1H, d, 6.0 Hz), 4.84 (2H, s), 3.83 (3H, s), 3.38 (1H, m), 2.11 1 (4H, q, 7.2 Hz), 1.26 (9H, s), 1.19 (6H, d, 7.2 Hz), 0.71 (6H, t, 7.4 Hz).
ES/MS: 445.2 (M+H) 462.2 (M + NH4).

Example 92

3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-(1-methylethyl)phenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0306] 

A. 3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-(1-methylethyl)phenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0307] 

[0308] 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-(1-methylethyl)phenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane 1(16 mg 0.26mmol) and sodium borohydride (9.8 mg, 0.26 mmol) are reacted in methanol and purified as described in Example 5F to give the title compound (93 mg, 80%).
H-NMR (ppm, CDCl₃): 7.63 (1H, d, 4.0 Hz), 7.08 (1H, s), 6.99 (1H, d, 9.0 Hz), 6.78 (1H, d, 4.0 Hz), 6.74 (1H, d, 9.0 Hz), 4.09 (1H, d, 8.2 Hz), 3.85 (1H. t, 8.2 Hz), 3.83 (3H, s), 3.72 (1H, d, 8.2 Hz), 3.25 (1H, m), 2.40 (1H, s), 2.12 (4H, q, 7.2 Hz), 1.17 (6H, d, 6.8 Hz), 1.02 (9H, s), 0.71 (6H, t, 7.2 Hz).
ESMS: 447.2 (M+1).

B. 3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-(1-methylethyl)phenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0309] 

[0310] Using a procedure analogous to Example 3,3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-(1-methylethyl)phenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (93 mg, 0.21 mmol) and 5N sodium hydroxide (1 ml, 5 mmol) are reacted and purified to give the title compound (66 mg, 73%).
H-NMR (ppm, CDCl₃): 7.69 (1H, d, 4.0 Hz), 7.08 (1H, s), 6.99 (1H, d, 6.0 Hz), 6.80 (1H, d, 4.0 Hz), 6.74 (1H, d, 6.0 Hz), 4.08 (1H, d, 8.0 Hz), 3.84 (1H, t, 8.0 Hz), 3.73 (1H, d, 8.0 Hz), 3.25 (1H, m), 2.13 (4H, q, 6.8 H₂), 1.17 (6H, d, 6.0 Hz), 1.02 (9H, s), 0.72 (6H, t, 7.0 Hz).
ES/MS: 431.2 (M-1) 450.2 (M + NH4).

Example 93

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-n-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0311] 

A. 3'-(4-hydroxy-3-n-propylphenyl)-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0312] 

[0313] To a mixture of o-propylphenol (1.09 g, 8.0 mol) and methyl, 5-(z/e-2-penten-3-yl)thiophene-2-carboxylate (0.21 g, 1.0 mmol) in methylene chloride (1 ml) is added BF3-etherate (56 mg, 0.2 mmol) under nitrogen and stirred for 16 h. The mixture is partitioned between satd NaHCO₃ and diethylether. The organic layer is washed with water, Na₂SO₄ dried, and concentrated. The excess phenol is removed from the residue by vacuum distillation at 70 °C/0.04 mm. The residue is chromatographed (4% EtOAc/hex) to give the title compound as an oil (0.27 g, 78%).
NMR (CDC13): 7.62 (d, 1H, J = 3.6 Hz); 6.96 (s, 1H); 6.94 (d, 1H, J = 7.3 Hz); 6.77 (d, 1H, J = 3.6 Hz); 6.66 (d, 1H, J = 8.0 Hz); 4.61 (s, 1H); 3.83 (s, 3H); 2.55 (t, 2H, J = 7.3 Hz); 2.11 (q, 4H, J = 7.2 Hz); 1.60 (m, 2H); 0.93 (t, 3H, J = 7.3 Hz); 0.71 (t, 6H, J = 7.2 Hz). FAB/MS: 347 M+1.

B. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-n-propylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0314] 

[0315] Using a procedure analogous to Example 91B, 3'-(4-hydroxy-3-n-propylphenyl)-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (0.27 g, 0.78 mmol) give the title compound as an oil (0.21 g, 60%).
NMR (CDC13): 7.61 (d, 1H, J = 4.4 Hz); 6.97 (s, 1H); 6.95 (d, 1H, J = 7.3 Hz); 6.77 (d, 1H, J = 4.4 Hz); 6.50 (d, 1H, J = 7.3 Hz); 4.83 (s, 2H); 3.83, (s, 3H); 2.61 (t, 2H, J = 7.3 Hz); 2.10 (q, 4H, J = 7.3 Hz); 1.59 (m, 2H); 1.26 (s, 9H); 0.90 (t, 3H, 7.3 Hz); 0.70 (t, 6H, 7.3 Hz).
FAB-MS: 444.3 molecular ion.

C. 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-n-propylphenyl)-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0316] 

[0317] To a mixture of 3'-[4-(2-oxo-3,3-dimetbylbutoxy)-3-n-propylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (0.199 g, 0.45 mmol) and MeOH (5 ml) is added NaBH₄ (17 mg, 0.45 mmol) in portions. After stirring for 4.5 h at room temperature, the reaction is concentrated and partitioned between satd NaHCO₃ and diethylether. The organic layer is washed with water, Na₂SO₄ dried, and concentrated to give the title compound as an oil (0.18 g, 90%).
NMR(CDCl3): 7.62 (d, 1H, J = 3.6 Hz); 7.02(1H, d, J = 7.5 Hz); 6.98 (s, 1H); 6.78 (d,1 H, 3.6 Hz); 6.73 (d, 1H, 7.5 Hz); 4.08 (1H, d, J = 9.0); 3.85 (t, 1H, J = 9.0); 3.83 (s, 3H); 3.71 (d, 1H, J = 9.0 Hz); 2.55 (t. 2H, 7.5 Hz); 2.40 (s, 1H); 2.12 (q, 4H, J = 7.6 Hz); 1.55 (m, 2H); 1.02 (s, 9H); 0.90 (t, 3H, J = 7.6 Hz); 0.71 (t, 6H, J = 7.2 Hz).
LC/MS: 447.2 M+1.

D. 3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-n-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0318] A mixture of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-n-propylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (0.18 g , 0.4 mmol), methanol (3 ml) and 5N NaOH (161 uL, 0.8 mmol) is heated to 50°C for 16 h. The reaction mixture is concentrated and the residue dissolved in water (4 mL). The solution is added conc. HCl, filtered with water wash, and air dried to give the title compound (0.16 g, 92%).
NMR(CDCl3): 7.69 (d, 1H, J = 4.0 Hz); 7.02 (d, 1 H, J = 7.5 Hz); 6.98 (s, 1H); 6.79 (d, 1 H, J = 4.0 Hz); 6.75 (d, 1H, J = 7.5 Hz); 5.29 (s, 1 H); 4.08 (d, 1 H, J = 9.0); 3.85 (t, 1H, J = 9.0 Hz); 3.70 (d, 1 H, J = 9.0 Hz); 2.55 (t, 2H, J = 7.5 Hz); 2.13 (q, 4H, J = 7.2 Hz); 1.55 (m,1H); 1.02 (s, 9H); 0.90 (t, 3H, H = 7.4 Hz); 0.72 (t, 6H, J = 7.4 Hz).
LC/MS: 413.2 M-1.

Example 94 and 95

Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-n-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0319] 

[0320] A mixture of racemic 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-n-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane (200 mg) is chromatographed on a ChiralPak AD column with IPA/heptane. Enantiomer 1 is further chromatographed on 4g of Silica Gel from 0% EtOAc/Hex to 50% EtOAc/Hex over 38 min at 12 ml/min to give pure enantiomer 1 (66 mg), Example 94. Enantiomer 2 from ChiralPak is further chromatographed on 4g of Silica Gel from 0% EtOAc/Hex to 50% EtOAc/Hex over 38 min at 12 ml/min. to give pure enantiomer 2 (66 mg), Example 95.

Enantiomer 1, Example 94

[0321] HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/85% heptane; 1 ml/m (flow rate); rt = 6.22 m; 225 nm.

Enantiomer 2, Example 95

[0322] HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/85% heptane; 1 ml/m (flow rate); rt = 9.0 m; 225 nm.

Example 96

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-i-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0323] 

A. 3'-(4-hydroxy-3-i-propylphenyl)-3'-[5-methoxycarbonyt-thiophen-2-yl]pentane.

[0324] 

[0325] Using a a procedure analogous to Example 93A, o-isopropylphenol (1.09 g, 8 mol) and methyl, 5-(E/Z-2-penten-3-yl)thiophene-2-carboxylate (0.21 g, 1.0 mol) give the title compound as an oil (0.28 g, 81%).
NMR (CDCl3): 7.62 (d, 1H, J = 4.0 Hz); 7.05 (s, 1H); 6.90 (d, 1H, J = 8.4 Hz); 6.78 (d, 1H, J = 4.0 Hz); 6.63 (d, 1H, J = 8.8 Hz); 4.58 (s, 1H); 3.83 (s, 3H); 3.15 (m, 1H); 2.11 (q, 4H, J = 7.2 Hz); 1.21 (d, 6H, J = 6.1 Hz); 0.71 (t, 6H, J = 7.4 Hz).
LC/MS: 347.2 M+1.

B. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-i-propylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0326] 

[0327] Using a procedure analogous to Example 91B, 3'-(4-hydroxy-3-i-propylphenyl)-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (0.28 g, 0.81 mmol) gives the title compound as an oil (0.13 g, 56%).
NMR (CDCl3): 7.61 (d, 1H, J = 4.4 Hz); 7.09 (s, 1H); 6.94 (d, 1H, J = 8.4 Hz); 6.77 (d, 1H, J = 4.4 Hz); 6.53 (d, 1H, J = 8.4 Hz); 4.84 (s, 2H); 3.83, (s, 3H); 3.38 (m, 2H); 2.11 (q; 4H, J = 7.2 Hz); 1.26 (s, 9H); 1.19 (d, 6H, J = 7.2 Hz); 0.70 (t, 6H, 7.2 Hz).
FAB-MS: 444.3 molecular ion.
LC/MS: 445.2 M+1 and 462.2 M+NH₄.

C. 3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-i-propylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0328] 

[0329] Using a procedure analogous to Example 2,3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-i-propylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane gives the title compound as an oil (0.09 g, 80%).
NMR(CDCl3): 7.62 (d, 1H, J = 3.6 Hz); 7.08 (s, 1H); 6.99 (1H, d, J = 8.8 Hz); 6.78 (d, 1H. 3.6 Hz); 6.73 (d, 1H, 8.8 Hz); 4.08 (1H, d, J = 8.8); 3.85 (t, 1H, J = 8.8); 3.83 (s, 3H); 3.71 (d, 1H, J = 8.8 Hz); 3.28 (m, 1H); 2.12 (q, 4H, J = 7.2 Hz); 1.17 (d, 6H; J = 6.8 Hz); 1.02 (s, 9H); 0.71 (t, 6H, J = 7.2 Hz).
LC/MS: 447.2 M+1.

D. 3'-[4-(2-Hydroxy-3,3,dimethylbutoxy)-3-i-propylphenyl]-3'-[5-carboxyl-thiophen-2-yl]pentane.

[0330] Using a procedure analogous to Example 3, 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-i-propylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (0.93 g, 0.21 mmol) and 5N NaOH aq (1 mL, 5 mmol) give the title compound as an oil (66 mg, 73%).
NMR(CDCl3): 7.69 (d,1H, J = 3.6 Hz); 7.08 (s, 1H); 6.98 (d, 1H, J = 8.1 Hz); 6.79 (d, 1H, J = 3.6 Hz); 6.74 (d, 1H, J = 8.1 Hz); 4.08 (d, 1H, J = 7.4); 3.85 (t, 1H, J = 7.4 Hz); 3.72 (d, 1H, J = 7.4 Hz); 3.25 (m, 1H); 2.13 (q, 4H, J = 6.8 Hz); 1.17 (d, 6H, J = 6.0 Hz); 1.02 (s, 9H); 0.72 (t, 6H, J = 6.8 Hz).
LC/MS: 450.2 M+NH₄.

Example 97 and Example 98

Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-i-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0331] 

[0332] A mixture of racemic 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-i-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane (22 mg) is chromatographed on a ChiralPak AD column with IPA/heptane) to give enantiomer 1 (8 mg), Example 97 and enantiomer 2 (7 mg), Example 98.
Enantiomer 1, Example 97
HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/85% heptane; 1 ml/m (flow rate); rt
Enantiomer 2, Example 98
HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/85% heptane; 1 ml/m (flow rate); rt= 6.53 m; 225 nm.

Example 99

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-ethylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0333] 

A. 3'-(4-hydroxy-3-ethylphenyl)-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0334] 

[0335] Using a procedure analogous to Example 93A, o-ethylphenol (0.98 g, 8.0 mol) and methyl, 5-(E/Z-2-penten-3-yl)thiophene-2-carboxylate (0.21g, 1.0 mol) give the title compound as an oil (0:26 g, 78%).
NMR (CDCl3): 7.62 (d, 1H, J = 4.0 Hz); 6.98 (s, 1H; 6.94 (d, 1H, J = 7.2 Hz); 6.78 (d, 1H, J = 4.0 Hz); 6.66 (d, 1H, J = 7.2 Hz); 4.60 (s, 1H); 3.83 (s, 3H); 2.59 (q, 2H, J = 7.7 Hz); 2.11 (q, 4H, J = 7.2 Hz); 1.19 (t, 3H, J = 7.6 Hz); 0.71 (t, 6H, J = 7.2 Hz).
FAB/MS: 333 M+1.

B. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-ethylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0336] 

[0337] Using a procedure analogous to Example 91B, 3'-(4-hydroxy-3-ethylphenyl)-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (0.26 g, 0.78 mmol) gives the title compound as an oil (0.24 g, 71%).
NMR (CDCl3): 7.61 (d, 1H, J = 3.6 Hz); 7.02 (s, 1H); 6.96 (d, 1H, J = 7.3 Hz); 6.77 (d, 1H, J = 3.6 Hz); 6.52 (d, 1H, J = 7.3 Hz); 4.83 (s, 2H); 3.83, (s, 3H); 2.66 (q, 2H, J = 7.3 Hz); 2:12 (q, 4H, J = 7.6 Hz); 1.21 (s, 9H); 1.18 (t, 3H, 7.3 Hz); 0.70 (t, 6H, 7.6 Hz).
LC/MS: 431.2M+1.

C. 3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-ethylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane.

[0338] 

[0339] Using a procedure analogous to Example 2, 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-ethylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane (0.22 g, 0.5 mmol) gives the title compound as an oil (0.16 g, 75%).
NMR(CDCl3): 7.62 (d, 1H, J = 3.2 Hz); 7.01 (1H, d, J = 7.4 Hz); 7.00 (s, 1H); 6.78 (d, 1H, 3.2 Hz); 6.73 (d, 1H, 7.4 Hz); 4.08 (1H, d, J = 8.1); 3.85 (t, 1H, J = 8.1); 3.83 (s, 3H); 3.70 (d, 1H, J = 8.1 Hz); 2.60 (t, 2H, 7.6 Hz); 2.40 (s, 1H); 2.12 (q, 4H, J = 7.2 Hz); 1.49 (t, 3H, J = 7.2 Hz); 1.02 (s, 9H); 0.71 (t, 6H, J = 7.2 Hz).
LC/MS showed a 433.2 M+1.

D. 3'-[4-(2-Hydroxy-3,3-dimethylbutoxy)-3-ethylphenyl]-3'-[5-carboxyl-thiophen-2-yl]pentane.

[0340] Using a procedure analogous to Example 3, 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-ethylphenyl]-3'-[5-methoxycarbonyl-thiophen-2-yl]pentane, methanol, and 5N NaOH at 50°C for 16 h to give the title compound (0.15 g, 94%).
NMR(DMSO-D6): 7.53 (d, 1H, J = 3.6 Hz); 7.01 (d, 1H, J = 8.8 Hz); 7.00 (s, 1H); 6.90 (d, 1H, J = 3.6 Hz); 6.85 (d, 1H, J = 8.8 Hz); 4.04 (d, 1H, J = 9.4); 3.86 (t, 1H, J = 9.4 Hz); 3.44 (d, 1H, J = 9.4 Hz); 2.56 (m, 2H); 2.09 (m, 4H); 1.08 (t, 3H, J = 8.0 Hz); 0.93 (s, 9H); 0.65 (t, 6H, J = 7.4 Hz).
LC/MS: 417.2 M-1.

Example 100 and Example 101

Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy-3-ethylphenyl)-3'-[5-carboxy-thiophen-2-yl]pentane.

[0341] 

[0342] A mixture of racemic 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-ethylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane (140 mg) is chromatographed on a ChiralPak AD column with IPA/heptane to give enantiomer 1 (59 mg), Example 100 and enantiomer 2 (51 mg), Example 101.
Enantiomer 1, Example 100
HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/85% heptane; 1 ml/m (flow rate);
rt = 4.42 m; 225 nm.
Enantiomer 2, Example 101
HPLC: ChiralPak AD (4.6X250 mm); 15% IPA/85% heptane; 1 ml/m (flow rate);
rt = 6.61 m; 225 nm.

Example 103

Preparation of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0343] 

A. 3'-[4-Hydroxy-3-methylphenyl]pentan-3-ol.

[0344] 

[0345] To a mixture of methyl, 4-hydroxy-3-methylbenzoate (21.8 g (0.13 mol) and 200 ml of THF is added 1M ethylmagnesium bromide/THF (432 mL (0.43 mol) under nitrogen. The mixture is stirred for 60 h and quenched with satd NaHCO3. The mixture is triturated five times with ether and the combined organic layers is washed with satd NaHCO3 and brine. The organic layer is Na2SO4 dried, filtered, and concentrated to give 27 g (99%) of the title compound.
NMR (CDC13): 7.12 (s, 1H); 7.03 (d, 1H, 8.0 Hz); 6.72 (d, 1H, J = 8.0 Hz); 4.69 (s, 1 H); 2.26 (s, 3H); 1.80 (m, 4H); 0.79 (t, 6H, 7.4 Hz).
ES/MS: 193 (M-1).

B. 3'-[4-Hydroxy-3-methylphenyl]-3'-(thiophen-2-yl)pentane.

[0346] 

[0347] To a mixture of thiophene (6 mL) and 3'-[4-hydroxy-3-methylphenyl]pentan-3-ol (0.92 g, 5 mmol) is added boron trifluoride etherate (100 µl, 0.8 mmol). The mixture is stirred for 96 h and partitioned between diethyl ether and satd NaHCO₃. The organic layer is washed with satd NaHCO₃, brine, Na₂SO₄ dried, and concentrated. The residue is chromatographed (12 g of SiO₂, Hex to 8% EtOAc/Hex) to give the title compound (0.53 g(41%).
[ES/MS 259.1 (M-1)].

C. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-(thiophen-2-yl)pentane.

[0348] 

[0349] Using a procedure analogous to Example 91B, 3'-[4-hydroxy-3-methylphenyl]-3'-(thiophen-2-yl)pentane (0.53 g, 2.2 mmol) gives the title compound as an oil (0.47 g, 64%).
NMR (CDCl3): 7.14 (d, 1H, J = 6.3 Hz); 7.03 (s, 1H); 6.98 (d, 1H, J = 9.0 Hz); 6.90 (m, 1H), 6.79 (d, 1H, J = 6.3 Hz), 6.52 (d, 1H, J = 9.0 Hz), 4.83 (s, 2H); 2.26 (s, 3H); 2.09 (m, 4H); 1.24 (s, 9H), 0.68 (t, 6H, 7.0 Hz).
ES/MS: 359.2 (M+1) 376.2 (M+NH4).

D. 3'-[4-(2-Hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-(thiophen-2-yl)pentane.

[0350] 

[0351] To a mixture of 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3'-(thiophen-2-yl)pentane (0.47 g (1.3 mmol) and diethyl ether (15 mL) is added 3 M methylmagnesium iodide/THF (1.3 ml, 3.9 mmol). After stirring for 2 h, the mixture is quenched with satd NaHCO₃ and triturated five times with diethyl ether. The combined organic layers is washed with water, brine, Na₂SO₄ dried, and concentrated to give the title compound (0.6 g, 99%).
NMR (CDCl3): 7.13 (d, 1H, J = 5.0 Hz); 7.02 (s, 1H); 7.03 (d, 1H. J = 8.4 Hz); 6.90 (m, 1H), 6.80 (d, 1H, J = 5.0 Hz), 6.70 (d, 1H, J = 8.4 Hz), 4.00 (d, 1H, J = 8.8 Hz); 3.83 (d, 1H, J = 8.8 Hz); 2.27 (s, 1H); 2.21 (s, 3H); 2.11 (m, 4H); 1.32 (s, 3H); 1.05 (s, 9H), 0.70 (t, 6H, 7.2 Hz).
ES-MS: 375.2 (M+1) 357.2 (M-H2O).

E. 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0352] 

[0353] To a 0 °C mixture of 3'-[4-(2-Hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-(thiophen-2-yl)pentane (0.6 g, 1.3 mmol) and cycloHex (20 ml) and ether (2 ml) is added 1.4 M sec-butyl lithium/cycloHex (2.85 ml, 3.2 mmol). The mixture is allowed to warm to RT and excess CO₂ gas is bubbled in. After two h, the mixture is partitioned between satd NaHCO₃ and diethyl ether. The aq phase is acidified with conc. perchloric acid and extracted into diethyl ether. The organic phase is washed with water, brine, Na₂SO₄ dried and concentrated. The residue is chromatographed (2% EtOAc/Hex to 50% EtOAc/Hex) to give of the title compound (0.3 g (44%).
NMR (CDCl₃): 7.69 (d, 1H, J = 3.6 Hz); 6.99 (s, 1H); 7.03 (d, 1H, J = 8.4 Hz); 6.80 (d, 1H, J = 3.6 Hz), 6.72 (d, 1H, J = 8.4 Hz), 4.00 (d, 1H, J = 8.8 Hz); 3.83 (d, I H, J = 8.8 Hz); 2.22 (s, 3H); 2.13 (q, 4H, J = 7.2 Hz); 1.33 (s, 3H); 1.04 (s, 9H), 0.72 (t, 6H, 7.2 Hz).
ES-MS: 417.3 (M-1) 436.3 (M+NH4).

Example 104 and Example 105

Preparation of enantiomers of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0354] A mixture of racemic 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane (∼290 mg) is chromatographed on a ChiralPak AD column with IPA/heptane to give enantiomer 1 (125 mg, 43), Example 104 and enantiomer 2 (140 mg, 48%), Example 105.
Enantiomer 1, Example 104
HPLC: ChiralPak AD (4.6X250 mm); 20% IPA/80% heptane; 1 ml/m (flow rate);
rt = 6.09 m; 225 nm..
Enantiomer 2, Example 105
HPLC: ChiralPak AD (4.6X250 mm); 20% IPA/80% heptane; 1 ml/m (flow rate);
rt = 8.00 m; 225 nm.

Example 106

[0355] Preparation of enantiomer 1 of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[5-(carboxymethylamino)carbonyl-thiophen-2-yl]pentane.

A. of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[5-(methylcarbonyl-methylamino)carbonyl-thiophen-2-yl]pentane.

[0356] To a mixture of enantiomer 1 of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane and DMSO (1 ml) is added EDCl (55 mg, 0.29 mmol), 0.5 M HOAT (523 uL, 0.26 mmol), methyl, aminoacetic acid hydrochloride (33 mg, 0.26 mmol), and triethylamine (136 uL, 1 mmol). The mixture is stirred for 72 h at RT, partitioned between diethyl ether and satd NaHCO3. The organic layer is washed with water, 2M HCl, water, satd NaHCO₃, then Na₂SO₄ dried, and concentrated. The residue is chromatographed (Hex to 30% EtOAc/Hex) to give the title compound (60 mg, 51%).
NMR (CDCl₃): 7.40 (d, 1H, J = 3.6 Hz); 7.04 (d, 1H, J = 8.8 Hz); 6.98 (s, 1H); 6.77 (d, 1H, J = 3.6 Hz), 6.71 (d, 1H, J = 8.8 Hz), 4.00 (d, 1H, J = 8.8 Hz); 6.53 (m, 1H); 4.18 (d, 1H, J = 4.8 Hz); 4.00 (d, 1H, J = 8.8 Hz); 3.84 (d, 1H, J = 8.8 Hz); 3.78 (s, 3H); 2.21 (s, 3H); 2.11 (q, 4H, J = 7.2 Hz); 1.33 (s, 3H); 1.04 (s, 9H), 0.70 (t, 6H, 7.2 Hz).
ES-MS: 490.4 (M+1) 488.4 (M-1).

B. 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[5-(carboxymethylamino)carbonyl-thiophen-2-yl]pentane, enantiomer 1.

[0357] 

[0358] To a mixture of enantiomer 1 of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-methylphenyl]-3'-[5,(methylcarbonyl-methylamino)carbonyl-thiophen-2-yl]pentane (60 mg, 0.12 mmol) and 50% methanol/water (0.5 ml) is added lithium hydroxide (6 mg, 0.24 mmol). The mixture is heated to 40°C for one h and concentrated. The residue is added ice and acidified with conc. HCl (pH∼1). The suspension is filtered, washed with water, and air dried to give the title compound as a solid (50 mg, 86%).
NMR (CDCl3): 7.45 (d, 1H, J = 4.0 Hz); 7.04 (d, 1H, J = 8.4 Hz); 6.97 (s, 1H); 6.79 (d, 1H, J = 4.0 Hz), 6.70 (d, 1H, J = 8.4 Hz), 4.00 (d, 1H, J = 8.8 Hz); 6.59 (m, 1H); 4.17 (s, 1H); 4.00 (d, I H, J = 8.8 Hz); 3.83 (d, 1H, J = 8.8 Hz); 3.02 (m, 1H); 2.20 (s, 3H); 2.11 (q, 4H, J = 7.2 Hz); 1.33 (s, 3H); 1.01 (s, 9H), 0.70 (t, 6H, 7.2 Hz).
ES/MS: 476.3 (M+1) 474.3 (M-1).

Example 107

Preparation of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0359] 

A. 3'-[4-Hydroxy-3-ethylphenyl]pentan-3-ol.

[0360] 

[0361] Using a procedure analogous to Example 103A, methyl, 4-hydroxy-3-ethylbenzoate (7.7g, 43 mmol) gives the title compound as an oil (9.2 g, 99%).
NMR (CDCl3): 7.13 (s, 1H); 7.04 (d, 1H, 8.0 Hz); 6.71 (d, 1H, J = 8.0 Hz); 4.65 (s, 1H); 2.64 (q, 2H. J = 7.2 Hz); 1.81 (m, 4H); 1.23 (m, 3H); 0.77 (t, 6H, 7.2 Hz).
ES/MS: 207.1 (M-1).

B. 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-ethylphenyl]pentan-3-ol.

[0362] 

[0363] Using a procedure analogous to Example 91B, 3'-[4-hydroxy-3-ethylphenyl]pentan-3-ol (9.2 g, 43 mmol) gives the title compound (11.9 g, 91%).
NMR (CDCl3): 7.14 (s, 1H); 7.10 (d, 1H, J = 8.0 Hz); 6.58 (d, 1H, J = 8.0 Hz); 4.85 (s, 2H); 2.71 (q, 2H. J = 7.6 Hz); 1.80 (m, 4H); 1.25 (s, 9H); 1.23 (t, 3H, J = 7.6 Hz); 0.76 (t, 6H, 7.2 Hz).
ES/MS: 289.1 (M+H-H2O).

C. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-ethylphenyl]-3'-(thiophen-2-yl)pentane.

[0364] 

[0365] Using a procedure analogous to Example 103B, 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-ethyl]phenyl]pentan-3-ol (10.9 g, 36 mmol) gives the title compound (6.1 g, 46%).
NMR (CDCl3): 7.14 (d, 1H, J = 1.2 Hz); 7.06 (s,1H); 6.96 (d, 1H, J = 8.4 Hz); 6.90 (t, 1H, J = 5.2 Hz); 6.80 (d, 1H, J = 1.2 Hz); 6.52 (d, 1H, J = 8.4 Hz); 4.83 (s, 2H); 2.67 (q, 2H, J = 7.2 Hz); 2.10 (q, 4H, J = 7.4); 1.25 (s, 9H); 1.20 (t, 3H, J = 7.2 Hz); 0.70 (t, 6H, 7.4 Hz).
ES/MS: 373.2 (M+1) 390.2 (M+NH4).

D. 3'-[4-(2-Hydroxy-2,3,3-trimethylbutoxy)-3,ethylphenyl]-3'-(thiophen-2-yl)pentane.

[0366] 

[0367] Using a procedure analogous to Example 103D, 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-ethylphenyl]-3'-(thiophen-2-yl)pentane (3.7 g, 10 mmol) gives the title compound after silica gel chromatography (1.8 g , 46%).
NMR (CDCl₃): 7.15 (d, 1H, J = 6.3 Hz); 7.04 (s, 1H); 7.03 (d, 1H, underlying); 6.90 (t, 1H, J = 5.2 Hz); 6.81 (m, 1H); 6.53 (d, 1H, J = 8.4 Hz); 4.00 (d, 1H, J = 8.4 Hz); 3.84 (d, 1H, J = 8.4 Hz); 2.62 (q, 2H, J = 7.6 Hz); 2.11 (q, 4H; J = 7.6); 1.33 (s, 3H); 1.16 (t, 3H, J = 7.6 Hz); 1.04 (s, 9H); 0.71 (t, 6H, 7.6 Hz).
ES/MS: 371.2 (M-H2O+1) 389.2 (M+1).

E.3'-[4-(2-Hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0368] 

[0369] Using a procedure analogous to Example 103E, 3'-[4-(2-Hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-(thiophen-2-yl)pentane (1.45 g, 3.7 mmol) gives the title compound (0.75 g, 46%).
NMR (CDCl3): 7.70 (d, 1H, J = 3.6 Hz); 7.02 (s, 1H); 7.03 (d, 1H, underlying); 6.80 (d, 1H, J = 3.6 Hz); 6.73 (d, 1H, J = 8.4 Hz); 4.00 (d, 1H, J = 8.8 Hz); 3.85 (d, 1H, J = 8.8 Hz); 2.62 (q, 2H, J = 7.6 Hz); 2.14 (q, 4H, J = 7.2); 1.33 (s, 3H); 1.17 (t, 3H, J = 7.6 Hz); 1.04 (s, 9H); 0.72 (t, 6H, 7.2 Hz).
ES/MS: 431.5 (M-1).

Example 108 and Example 109

Preparation of enantiomers of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

enantiomer 1

enantiomer 2

[0370] A mixture of racemic 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane (0.93 g) is chromatographed (ChiralPak AD column; 5% ethyl alcohol/95% Hept to give enantiomer 1 (453 mg), Example 108 and enantiomer 2 (438 mg), Example 109.
Enantiomer 1, Example 108
HPLC: ChiralPak AD (4.6X250 mm); 5% IPA/95% heptane; 1 ml/m (flow rate); rt = 10.2 m; 225 nm..
Enantiomer 2, Example 109
HPLC: ChiralPak AD (4.6X250 mm); 5% IPA/95% heptane; 1 ml/m (flow rate); rt = 13.0 m; 225 nm.

Example 110

Preparation of enantiomer 1 of d-3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-[5-(carboxy-1-ethylamino)carbonyl-thiophen-2-yl]pentane,.

[0371] 

A. Enantiomer 1 of d-3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-[5-(methoxycarbonyl-1-ethylamino)carbonyl-thiophen-2-yl]pentane.

[0372] 

[0373] Using a procedure analogous to Example 106A, enantiomer 1 of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane (310 mg, 0.71 mmol) and d-alanine methylester HCl give the title compound (173 mg, 47%).
NMR (CDCl3): 7.39 (d, 1H, J = 4.0 Hz); 7.01 (s, 1H); 7.02 (d, 1H, underlying); 6.78 (d, 1H, J = 4.0 Hz); 6.64 (d, 1H, J = 8.0 Hz); 6.38 (d, 1H, J = 6.5 Hz); 4.74 (m, 1H); 4.00 (d, 1H, J = 7.2 Hz); 3.85 (d, 1H, J = 7.2 Hz); 3.77 (s, 3H); 2.62 (q, 2H, J = 7.6 Hz); 2.22 (s, 1H); 2.11 (q, 4H, J = 7.6); 1.48 (d, 3H, J = 7.2 Hz); 1.33 (s, 3H); 1.17 (t, 3H, J = 7.6 Hz); 1.04 (s, 9H); 0.71 (t, 6H, 7.2 Hz).

B. Enantiomer 1 of d-3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-[5-(carboxy-1-ethylamino)carbonyl-thiophen-2-yl]pentane.

[0374] 

[0375] Using a procedure analogous to Example 106B, enantiomer 1 of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-ethylphenyl]-3'-[5-(methoxycarbonyl-1-ethylamino)carbonyl-thiophen-2-yl]pentane (173 mg, 0.33 mmol) gives the title compound as a solid (147 mg, 87%).
NMR (CDCl₃): 7.43 (d, 1H, J = 3.6 Hz); 7.01 (s, 1H); 7.02 (d, 1H, underlying); 6.79 (d, 1H, J = 3.6 Hz); 6.73 (d, 1H, J = 8.0 Hz); 6.35 (d, 1H, J = 8.0 Hz); 4.70 (m, 1H); 4.00 (d, 1H, J = 8.8 Hz); 3.84 (d, 1H, J= 8.8 Hz); 2.61 (q, 2H, J = 7.6 Hz); 2.10 (q, 4H, J = 7.2); 1.52 (d, 3H, J = 7.6 Hz); 1.32 (s, 3H); 1.15 (t, 3H, J = 7.6 Hz); 1.03 (s, 9H); 0.70 (t, 6H, 7.2 Hz).
ES/MS: 504.2 (M+1) 502.3 (M-1).

Example 111

Preparation of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0376] 

A. 3'-[4-Hydroxy-3-n-propylphenyl]pentan-3-ol.

[0377] 

[0378] Using a procedure analogous to Example 103A, ethyl, 4-hydroxy-3-n-propylbenzoate (5.0, 24 mmol) gives the title compound as an oil (5.7 g, 99%).
NMR (CDC13): 7.09 (s, 1H); 7.04 (d, 1H, 8.4 Hz); 6.71 (d, 1H, J = 8.4 Hz); 4.62 (s, 1H); 3.75 (m, 1H); 2.59 (t, 2H. J = 7.4 Hz); 1.80 (m, 4H); 1.64 (m, 2H); 0.94 (t, 3H, J = 7.4 Hz); 0.76 (t, 6H, 7.6 Hz).
ES/MS: 205.1 (M+H-H2O).

B. 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-n-propylphenyl]pentan-3-ol.

[0379] 

[0380] Using a procedure analogous to Example 91B, 3'-[4-hydroxy-3-n-propylphenyl]pentan-3-ol (5.7 g, 24 mmol) gives the title compound (7.1 g, 93%). NMR (CDCl3): 7.11 (s, 1H); 7.09 (d, 1H, J = 8.0 Hz); 6.57 (d, 1H, J = 8.0 Hz); 4.84 (s, 2H); 2.66 (t, 2H. J = 7.6 Hz); 1.80 (m, 4H); 1.65 (m, 2H); 1.26 (s, 9H); 0.95 (t, 3H, J = 7.2 Hz); 0.76 (t, 6H, 7.4 Hz).
ES/MS: 303.1 (M- H2O+1).

C. 3'-[4-(2-Oxo-3,3-dimethylbutoxy)-3-n-propylphenyl]-3'-(thiophen-2-yl)pentane.

[0381] 

[0382] Using a procedure analogous to Example 103B, 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-n-propylphenyl]pentan-3-ol (7.1 g, 22 mmol) gives the title compound after silica gel chromatography (4.0 g, 47%).
NMR (CDCl3): 7.12 (d, 1H, J = 1.2 Hz); 7.03 (s, 1H); 6.97 (d, 1H, J = 8.0 Hz); 6.90 (t, 1H, J = 5.2 Hz); 6.80 (d, 1H, J = 1.2 Hz); 6.51 (d, 1H, J = 8.0 Hz); 4.82 (s, 2H); 2.62 (t, 2H, J = 7.8 Hz); 2.09 (q, 4H, J = 7.6); 1.59 (m, 2H); 1.25 (s, 9H); 0.90 (m, 3H); 0.71 (t, 6H, 7.6 Hz).
ES/MS: 387.2 (M+1) 404.2 (M+NH4).

D. 3'-[4-(2-Hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-(thiophen-2-yl)pentane.

[0383] 

[0384] Using a procedure analogous to Example 103D, 3'-[4-(2-oxo-3,3-dimethylbutoxy)-3-n-propylphenyl]-3'-(thiophen-2-yl)pentane (1.3 g, 3.4 mmol) gives the title compound (1.2 g , 86 %).
NMR (CDCl3): 7.13 (d, 1H, J = 6.0 Hz); 7.03 (s, 1H); 7.04 (d, 1H, underlying); 6.90 (t, 1H, J = 5.2 Hz); 6.8 (d, 1H, J = 6.0 Hz); 6.73 (d, 1H, J = 8.4 Hz); 3.99 (d, 1H, J = 8.4 Hz); 3.84 (d, 1H, J = 8.4 Hz); 2.57 (q, 2H, J = 7.6 Hz); 2.32 (s, 1H); 2.11 (q, 4H, J = 7.6); 1.56 (m, 2H); 1.32 (s, 3H); 1.04 (s, 9H); 0.90 (t, 3H, J = 7.4 Hz); 0.71 (t, 6H, 7.6 Hz).
ES/MS: 403.2 (M+1).

E. 3'-[4-(2-Hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0385] 

[0386] Using a procedure analogous to Example 103E, 3'-[4-(2-Hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-(thiophen-2-yl)pentane (1.2 g, 2.9 mmol) gives the title compound (0.53 g, 41%).
NMR (CDCl3): 7.70 (d, 1H, J = 3.6 Hz); 7.03 (d, 1H, J = 8.0 Hz); 6.98 (s, 1H); 6.80 (d, 1H, J = 3.6 Hz); 6.74 (d, 1H, J = 8.0 Hz); 4.00 (d, 1H, J = 8.8 Hz); 3.84 (d, 1H, J = 8.8 Hz); 2.57 (t, 2H, J = 8.0 Hz); 2.13 (q, 4H, J = 7.0); 1.57 (m, 2H); 1.33 (s, 3H); 1.05 (s, 9H); 0.92 (t, 3H, J = 7.2 Hz); 0.72 (t, 6H, 7.0 Hz).
ES/MS: 445.5 (M-1).

Example 114

Preparation of enantiomer 1 of d-3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-[5-(carboxy-1-ethylamino)carbonyl-thiophen-2-yl]pentane.

[0387] 

A. Enantiomers of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane.

[0388] 

[0389] A racemic mixture of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane (0.265 g) is chromatographed (ChiralPak AD column; 0.1%TFA in IPA/heptane to give enantiomer 1 (130 mg; TFA occluded, ∼49%), Example 112 and enantiomer 2 (105 mg; TFA occluded, ∼40%), Example 113.
Enantiomer 1, Example 112
HPLC: ChiralPak AD (4.6X250 mm); 20% IPA/80% heptane; 1 ml/m (flow rate); rt = 5.3 m; 225 nm..
Enantiomer 2, Example 113
HPLC: ChiralPak AD (4.6X250 mm); 20% IPA/80% heptane; 1 ml/m (flow rate); rt = 6.7 m; 225 nm.

B. Enantiomer 1 of d-3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-[5-(methoxycarbonyl-1-ethylamino)carbonyl-thiophen-2-yl]pentane.

[0390] 

[0391] Using a procedure analogous to Example 106A, enantiomer 1 of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-[5-carboxy-thiophen-2-yl]pentane (130 mg, 0.3 mmol) and d-alanine methylester HCl give the title compound (49 mg, 32%).
NMR (CDCl3): 7.39 (d, 1H, J = 3.6 Hz); 6.99 (s, 1H); 7.02 (d, 1H, J = 8.4 Hz); 6.76 (d, 1H, J = 3.6 Hz); 6.73 (d, 1H, J = 8.4 Hz); 6.38 (d, 1H, J = 7.0 Hz); 4.73 (m, 1H); 4.00 (d, 1H, J = 7.6 Hz); 3.85 (d, 1H, J = 7.6 Hz); 3.77 (s, 3H); 2.55 (t, 2H, J = 8.0 Hz); 2.21 (s, 1H); 2.11 (q, 4H, J = 7.2); 1.56 (m, 2H); 1.47 (d, 3H, J = 6.8 Hz); 1.33 (s, 3H); 1.03 (s, 9H); 0.91 (t, 3H, J = 7.6 Hz); 0.71 (t, 6H, 7.4 Hz).
ES/MS: 532.2 (M+1) 530.3 (M-1).

C. Enantiomer 1 of d-3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-[5-(carboxy-1-ethylamino)carbonyl-thiophen-2-yl]pentane.

[0392] 

[0393] Using a procedure analogous to Example 106B, enantiomer I of 3'-[4-(2-hydroxy-2,3,3-trimethylbutoxy)-3-n-propylphenyl]-3'-[5-(methoxycarbonyl-1-ethylamino)carbonyl-thiophen-2-yl]pentane (48 mg, 0.1 mmol) gives the title compound as a solid (38 mg, 81%).
NMR (CDCl3): 7.43 (d, 1H, J = 4.0 Hz); 6.97 (s, 1H); 7.02 (d, 1H, J = 8.4 Hz); 6.79 (d, 1H, J = 4.0 Hz); 6.73 (d, I H, J = 8.4 Hz); 6.28 (d, 1H, J = 7.0Hz); 4.70 (m, 1H); 3.99 (d, 1H, J = 8.8 Hz); 3.84 (d, 1H, J = 8.8 Hz); 2.56 (t, 2H, J = 7.8 Hz); 2.11 (q, 4H, J = 8.0); 1.56 (m, 2H); 1.53 (d, 3H, J = 7.6 Hz); 1.33 (s, 3H); 1.04 (s, 9H); 0.91 (t, 3H, J = 7.8 Hz); 0.71 (t, 6H, 8.0 Hz).
ES/MS: 518.2 (M+1) 516.2 (M-1).

Example 118

Preparation of N-methyl-2-[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl} -3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid.

[0394] 

A. 5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophene-2-carboxylic acid.

[0395] 

[0396] Using a procedure analogous to Example 47, 5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophene-2-carboxylic acid methyl ester, (Example IF) (6.68 g, 20.12 mmol) gives the title compound (6.30 g, 19.81 mmol, 90%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 6.9 Hz, 6H), 2.11 (q, J = 6.9 Hz, 4H), 2.23 (s, 3H), 2.48 (s, 3H), 6.61 (s, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.94-7.00 (m, 2H). LC/MS (m/z): calcd for C₁₈H₂₂O₃S: 318.1; found: 318.1.

B. N-methyl-2-{5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophene-2-carbonyl}-methylamino)-acetic acid methyl ester.

[0397] 

[0398] Using a procedure analogous to Example 38, from [1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophene-2-carboxylic acid (1.90 g, 5.96 mmol) and sarcosine methyl ester hydrochloride (0.89 g, 6.55 mmol) gives the title compound (1.99 g, 4.94 mmol, 83 %). ¹H NMR (CDCl₃), d 0.70 (t, J = 7.1 Hz, 6H), 2.01-2.09 (m, 4H), 2.21 (s, 3H), 2.24 (s, 3H), 3.10 (s, 3H), 3.74 (s, 3H), 4.20 (bs, 2H), 6.52 (s, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.90-7.01 (m, 2H). LC/MS (m/z): calcd for C₂₂H₃₀NO₄S (M+H)⁺: 404.2; found: 404.2.

C. N-methyl-2-[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid methyl ester

[0399] 

[0400] Using a procedure analogous to Example 1G, from 2-({5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophene-2-carbonyl}-methylamino)-acetic acid methyl ester (1.99 g, 4.94 mmol) gives the title compound (1.14 g, 2.28 mmol, 46%). ¹H NMR (CDCl₃), d 0.70 (t, J = 7.4 Hz, 6H), 1.27 (s, 9H), 2.00-2.14 (m, 4H), 2.24 (s, 3H), 2.26 (s, 3H), 3.01 (s, 3H), 3.75 (s, 3H), 4.16-4.24 (bs, 2H), 4.84 (s, 2H), 6.49-6.53 (m, 2H), 6.90-7.03 (m, 2H). LC/MS (m/z): calcd for C₂₈H₄₀NO₅S (M+H)⁺: 502.7; found: 502.2.

D. N-methyl-2-[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl} -3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid

[0401] 

[0402] To a mixture of 2-[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl)-]-ethyl-propyl}-3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid methyl ester (0.16 g, 0.32 mmol) and THF (2 mL) is added and H₂O (2mL) and 1.0 M NaOH (0.35 mL, 0.35 mmol). The reaction is stirred at RT overnight, acidified with 0.1 M HCl to pH 3-4 and extracted with EtOAc (2 x 30 mL). The organic layer is MgSO₄ dried and concentrated to give the title compound (0.14 g, 90%). ¹H NMR (CDCl₃), δ 0.71 (t, J = 7.2 Hz, 6H), 1.27 (s, 9H), 2.02-2.10 (m, 4H), 2.24 (s, 3H), 2.26 (s, 3H), 3.12 (s, 3H), 4.21 (bs, 2H), 4.86 (s, 2H), 6.49-6.55 (m, 2H), 6.96-7.03 (m, 2H). LC/MS (m/z): calcd for C₂₇H₃₈NO₅S (M+H)⁺: 488.7; found: 488.2.

Example 119

Preparation of N-methyl-2-[(5-{1-ethyl-1 -[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid methyl ester.

[0403] 

[0404] Using a procedure analogous to Example 2, N-methyl-2-[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid methyl ester (0.96 g, 1.92 mmol) gives the title compound (0.75 g, 1.49 mmol, 78%). ¹H NMR (CDCl₃), d 0.71 (t, J= 7.0 Hz, 6H), 1.03 (s, 9H), 2.04-2.14 (m, 4H), 2.21 (s, 3H), 2.24 (s, 3H), 3.09 (s, 3H), 3.71 (dd, J = 8.4,2.6 Hz, 1H), 3.75 (s, 3H), 3.87 (t, J = 8.9 Hz, 1H), 4.10 (dd, J= 9.2, 2.6 Hz, 1H), 4.20 (bs, 2H), 6.52 (s, 1H), 6.72 (d, J = 8.7 Hz, 1H), 7.00-7.07 (m, 2H). LC/MS (m/z): calcd for C₂₈H₄₂NO₅S (M+H)⁺: 504.7; found: 504.2.

Example 120 and 121

Preparation of enantiomers of N-methyl-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid methyl ester.

[0405] 

[0406] A racemic mixture of N-methyl-2-[(5-{1-ethyl-1-[4-(2-hydroxy 3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid methyl ester (740 mg) is chromatographed (CHIRALPAK AD column, 40% i-PrOH/Hept) to give enantiomer 1 of the title compound (Example 120) (205 mg, 28%) and enantiomer 2 of the title compound (Example 121) (179 mg, 24%).
Enantiomer 1, Example 120 :
rt = 7.1 m
NMR & LC/MS: Identical to the racemic material, Example 119.
Enantiomer 2, Example 121 :
rt = 22.8 m
NMR & LC/MS: Identical to the racemic material, Example 119.

Example 122

Preparation of enantiomer 1 of N-methyl-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl)-3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid.

[0407] 

[0408] Using a procedure analogous to Example 47, enantiomer 1 of N-methyl-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl} -3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid methyl ester (200 mg) yields the title compound (189 mg, 97%). ¹H NMR (CDCl₃), d 0.71 (t, J= 7.2 Hz, 6H), 1.02 (s, 9H), 2.01-2.13 (m, 4H), 2.20 (s, 3H), 2.24 (s, 3H), 3.12 (s, 3H), 3.72 (dd, J = 8.8,2.7 Hz, ¹H), 3.88 (t, J = 8.9 Hz, ¹H), 4.12 (dd, J = 9.1, 2.7 Hz, 1H), 4.21 (s, 2H), 6.53 (s, 1H), 6.72 (d, J = 8.6 Hz, 1H), 7.00-7.06 (m, 2H). LC/MS (m/z): calcd for C₂₇H₄₀NO₅S (M+H)⁺: 490.7; found: 490.3.

Example 123

Preparation of enantiomer 2 of N-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl]-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid.

[0409] 

[0410] Using a procedure analogous to Example 47, enantiomer 2 of N-methyl-2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-methylamino]-acetic acid methyl ester (172 mg, 0.34 mmol) yields the title compound (168.8mg, 98%). ¹H NMR and LC/MS (m/z): identical to Example 122.

Example 124

Preparation of 2-(5- {1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophen-2-yl-methoxy)acetic acid.

[0411] 

A. 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methylphenol}-1-ethyl-propyl)-3-methyl-thiophene-2-carboxylic acid methyl ester.

[0412] 

[0413] To a mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester (Example 2) (1.15 g, 2.66 mmol), imidazole (0.27 g, 4.00 mmol), and DMF (15 mL) is added TBSCI (0.54 g, 2.80 mmol). The reaction is stirred for 24 h. The reaction is diluted with Et₂O (120 mL) and washed with 0.1 M HCl (3 x 40 ml). The organic layer is MgSO₄ dried and concentrated. The resulting residue is chromatographed to give the title compound (0.94 g, 64%). ¹H NMR (CDCl₃), δ 0.01 (s, 3H), 0.06 (s, 3H), 0.65 (t, J= 7.4 Hz, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 2.00-2.14 (m, 4H), 2.14 (s, 3H), 2.43 (s, 3H), 3.67 (dd, J = 5.8, 3.4 Hz, 1H), 3.74 (s; 3H), 3.85 (dd, J = 9.8, 5.8 Hz, 1H), 3.98 (dd, J = 9.8, 3.4 Hz, 1H), 6.56 (s, 1H), 6.68 (d, J = 8.3 Hz, 1H), 6.96-7.03 (m, 2H). LC/MS (m/z): calcd for C₃₁H₅₁O₄SSi (M+H)⁺: 547.9; found: 547.2.

B. 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimetbyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophen-2-yl-methanol.

[0414] 

[0415] To a 0°C solution of 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-carboxylic acid methyl ester (0.94 g, 1.71 mmol) and THF (50 mL)is added LAH (71 mg, 1.89 mmol). The mixture is stirred for 10 m, warmed to RT and stirred for 2 h. The reaction is quenched with H₂O (70 ul), 15% NaOH (70 uL) and H₂O (210 uL) and diluted with EtOAc (50 mL). The mixture is filtered through diatomaceous earth and concentrated to give the title compound (0.89 g, 1.72 mmol, 100%). ¹H NMR (CDCl₃), δ 0.07 (s, 3H), 0.12 (s, 3H), 0.72 (t, J = 7.4 Hz, 6H), 0.91 (s, 9H), 0.98 (s, 9H), 2.01-2.14 (m, 4H), 2.19 (s, 3H), 2.21 (s, 3H), 3.68 (dd, J = 5.3, 3.4 Hz, 1H), 3.86 (dd, J = 9.0, 5.3 Hz, 1H), 3.98 (dd, J = 9.0, 3.4 Hz, 1H), 4.67 (s, 2H), 6.54 (s, 1H), 6.67 (d, J = 8.1 Hz, 1H), 7.00-7.06 (m, 2H). LC/MS (m/z): calcd for C₃₀H₅₀O₃SSi M⁺: 518.9; found: 518.0.

C. 2-[5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophen-2-ylmethoxy]-acetic acid methyl ester.

[0416] 

[0417] T a 0 °C solution of 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophen-2-yl-methanol (0.96 g, 1.85 mmol) in THF (10 mL) is added 60% NaH (81 mg, 2.0 mmol) and stirred for 20 m. The mixture is added methyl bromoacetate (0.21 mL, 2.22 mmol)warmed to RT, and stirred overnight. The reaction is quenched with satd NH₄Cl (10 mL), diluted with H₂O (10 mL), and extracted with EtOAc (2 x 20 mL). The combined organic layers is MgSO₄ dried and concentrated. The resulting residue is chromatographed to give the title compound (0.33 g, 0.57 mmol, 31%). ¹H NMR (CDCl₃), δ 0.06 (s, 3H), 0.12 (s, 3H), 0.70 (t, J = 7.3 Hz, 6H), 0.91 (s, 9H), 0.97 (s, 9H), 2.01-2.10 (m, 4H), 2.19 (s, 3H), 2.20 (s, 3H), 3.67 (dd, J= 5.8,3.4 Hz, 1H), 3.76 (s, 3H), 3.85 (dd, J = 9.8, 5.8 Hz, 1H), 3.98 (dd, J= 9.8, 3.4 Hz, 1H), 4.09 (s, 2H), 4.64 (s, 2H), 6.53 (s, 1H), 6.67 (d, J = 8.3 Hz, 1H), 7.00-7.06 (m, 2H). LC/MS (m/z): calcd for C ₃₃H₅₈NO₅SSi (M+NH₄)⁺: 608.9; found: 608.3.

D. 2-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl)-3-methyl-thiophen-2-yl-methoxy)-acetic acid.

[0418] 

[0419] A solution of 2-[5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl} -1-ethyl-propyl)-3-methyl-thiophen-2-ylmethoxy]-acetic acid methyl ester (0.33 g, 0.57 mmol), 1.0 M TBAF/THF (0.62 m L, 0.62 mmol) and THF (4 mL) is refluxed for 3h. The mixture filtered through silica gel, washed with EtOAc and concentrated. The resulting residue is hydrolyzed using a procedure analogous to Example 47 to give the title compound (0.13 g, 0.28 mmol) in an overall yield of 49%. ¹H NMR (EDCl₃), δ 0.71 (t, J = 7.4 Hz, 6H), 1.02 (s, 9H), 2.01-2.10 (m, 4H), 2.19 (s, 3H), 2.20 (s, 3H), 2.21 (bs, 2H), 3.72 (dd, J = 8.8, 2.9 Hz, 1H), 3.87 (t, J = 8.8 Hz, 1H), 4.08-4.1 (m, 2H), 4.16 (s, 1H), 4.66 (s, 1H), 5.24 (s, 1H), 6.54 (d, J = 3.4 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 7.01-7.08 (m, 2H). LC/MS (m/z): calcd for C₂₆H₃₇O₅S (M-H)^-: 461.7; found: 461.2.

Example 125

Preparation of 1-{4-[1-ethyl-1-(5-hydroxymethyl-4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol.

[0420] 

[0421] A solution of 1-{4-[1-ethyl-1-(5-hydroxymethyl-4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol, Example B ( 71.5 mg, 0.14 mmol) in THF (3 mL) is treated with 1.0 M TBAF (0.15 mL, 0.15 mmol). The reaction is refluxed for 14 h, diluted with EtOAc (20 mL), washed with H₂O (10 mL), MgSO₄ dried, and concentrated. The resulting residue is chromatographed to give the title compound (41.1 mg, 0.10 mmol, 71%). %). ¹H NMR (CDCl₃), δ 0.71 (t, J = 6.8 Hz, 6H), 1.02 (s, 9H), 2.02-2.11 (m, 4H), 2.19 (s, 3H), 2.21 (s, 3H), 2.44 (d, J = 2.9 Hz, 1H), 3.71 (dt, J = 8.9, 2.4 Hz, 1H), 3.87 (t, J = 8.9 Hz, 1H), 4.10 (dd, J = 8.9, 2.4 Hz, 1H), 4.66 (d, J = 5.4 Hz, 2H), 6.53 (s, 1H), 6.72 (d, J = 8.3 Hz, 1H), 7.02-7.08 (m, 2H). LC/MS (m/z): calcd for C₂₄H₃₆NaO₃S (M+Na)⁺: 427.6; found: 427.2.

Example 126 and 127

Preparation of enantiomers of 1-{4-[1-ethyl-]-1-(5-hydroxymethyl-4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol.

[0422] 

[0423] A racemic mixture of 1-{4-[1-ethyl-1-(5-hydroxymethyl-4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol (37.5 mg) is chromatographed (CHIRALPAK AD column, 40% i-PrOH/Hept) to give enantiomer 1 of the title compound, Example126 (3.6 mg, 10%) and enantiomer 2 of the title compound, Example 127 (2.8 mg, 7%).
Example 126, Enantiomer 1
rt = 5.3 m
NMR & LC/MS: Identical to the racemic material, Example 125.
Example 127, Enantiomer 2
rt = 8.5 m
NMR & LC/MS: Identical to the racemic material, Example 125.

Example 128

Preparation of sodium salt of enantiomer 1 of 2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl} -3-methyl-thiophene-2-carbonyl)-amino]-acetic acid.

[0424] 

[0425] A solution of enantiomer 1 of 2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino] -acetic acid, Example 48 (597 mg, 1.26 mmol) in CH₃OH (5 mL) is treated with 0.5 M NaOCH₃ (2.7 mL, 1.4 mmol) and stirred for 5 m. The mixture is concentrated to give the title compound (626 mg. 1.26 mmol, 100%). ¹H NMR (CD₃OD), δ 0.75 (t, J= 7.1 Hz, 6H), 1.05 (s, 9H), 2.10-2.20 (m, 4H), 2.23 (s, 3H), 2.50 (s, 3H), 3.66 (dd, J = 7.9, 3.0 Hz, 1H), 3.89 (s, 2H), 3.90-3.95 (m, 1H), 4.16 (dd, J = 10.1, 3.0 Hz, 1H), 6.72 (s, 1H), 6.83 (d, J= 8.8 Hz, 1H), 7.02-7.12 (m, 2H). LC/MS (m/z): calcd for C₂₆H₃₈NO₅S (M+H)⁺: 476.2; found: 476.2

Example 129

Preparation of sodium salt of enantiomer 2 of [(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid.

[0426] 

[0427] Using a procedure analogous to Example 128, enantiomer 2 of 2-[(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid (Example 49) (0.69 g,, 1.15 mmol) gives the title compound (0.69 g, 1.15 mmol, 100%). ¹H NMR and LC/MS: identical to Example 128.

Example 130

Preparation of 2-[N-acetyl-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophen-2-ylmethyl)-amino]-acetic acid.

[0428] 

A. Preparation of 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-carbaldehyde.

[0429] 

[0430] Using a procedure analogous to Example 41, 1-{4-[1-ethyl-1-(5-hydroxymethyl-4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol (Example 124B) (0.88 g, 1.69 mmol) gives the title compound (0.77 g, 1.49 mmol, 88%). ¹H NMR (CDCl₃), δ 0.07 (s, 3H), 0.12 (s, 3H), 0.72 (t, J= 7.4 Hz, 6H), 0.91 (s, 9H), 0.98 (s, 9H), 2.12 (q, J= 7.4 Hz, 4H), 2.21 (s, 3H), 2.50 (s, 3H), 3.68 (dd, J = 5.4, 3.5 Hz, 1H), 3.86 (dd, J = 9.9, 5.4 Hz, 1H), 3.98 (dd, J = 9.9, 3.5 Hz, 1H), 6.64 (s, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.95-7.03 (m, 2H), 9.92 (s, 1H). LC/MS (m/z): calcd for C₃₀H₄₉O₃SSi (M+H)⁺: 517.9; found: 517.2

B. 2-{[5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophen-2-ylmethyl]-amino}-acetic acid methyl ester.

[0431] 

[0432] A mixture of 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-carbaldehyde (2.11 g, 4.09 mm) and glycine methyl ester hydrochloride (0.56 g, 4.50 mmol) with Et₃N (0.74 mL, 5.3 mmol) is treated with Ti(Oi-Pr)₄ (1.6 mL, 5.3 mmol) at RT for 1h. It is diluted with CH₃OH (20 mL), treated with NaB(CN)H₃ (282 mg, 4.5 mmol). The reaction is stirred overnight. It is then quenched with H₂O (3 mL) and stirred at RT for 1h, and filtered through silica gel washed with EtOAC (100 mL) and concentrated. Chromatographic purification gives the title compound (1.54 g, 2.61 mmol, 64%).
¹H NMR (CDCl₃), δ 0.06 (s, 3H), 0.12 (s, 3H), 0.70 (t, J = 6.9 Hz, 6H), 0.91 (s, 9H), 0.97 (s, 9H), 2.02-2.10 (m, 4H), 2.13 (s, 3H), 2.20 (s, 3H), 3.45 (s, 2H), 3.67 (dd, J = 5.4, 3.4 Hz, 1H), 3.73 (s, 3H), 3.82-3.87 (m, 3H), 3.98 (dd, J = 9.6, 3.4 Hz, 1H), 6.49 (s, 1H), 6.67 (d, J = 8.3 Hz, 1H), 7.00-7.05 (m, 2H). LC/MS (m/z): calcd for C₃₃H₅₅NO₄SSi (M)⁺: 589.9; found: 589.0.

C. 2-{[5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methy]-thiophen-2-ylmethyl]-amino}-acetic acid methyl ester.

[0433] 

[0434] Using a procedure analogous to Example 41, 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-carbaldehyde (additional example Lu-13-A) (2.11 g, 4.09 mm) and glycine methyl ester hydrochloride (0.56 g, 4.50 mmol) give the title compound (1.54 g, 2.61 mmol, 64%). %). ¹H NMR (CDCl₃), δ 0.06 (s, 3H), 0.12 (s, 3H), 0.70 (t, J = 6.9 Hz, 6H), 0.91 (s, 9H), 0.97 (s, 9H), 2.02-2.10 (m, 4H), 2.13 (s, 3H), 2.20 (s, 3H), 3.45 (s, 2H), 3.67 (dd, J = 5.4, 3.4 Hz, 1H), 3.73 (s, 3H), 3.82-3.87 (m, 3H), 3.98 (dd, J = 9.6, 3.4 Hz, 1H), 6.49 (s, 1H), 6.67 (d, J = 8.3 Hz, 1H), 7.00-7.05 (m, 2H). LC/MS (m/z): calcd for C₃₃H₅₅NO₄SSi (M)⁺: 589.9; found: 589.0.

D. 2-{N-Acetyl-[5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophen-2-ylmethyl]-amino}-acetic acid methyl ester.

[0435] 

[0436] To a 0° C solution of 2-{[5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophen-2-ylmethyl]-amino}-acetic acid methyl ester (1.54 g, 2.61 mmol) in CH₂Cl₂ (10 mL) is added acetyl chloride (0.20 mL, 2.88 mmol). The reaction is stirred at RT for 1h, diluted with CH₂Cl₂ (100 mL), washed with 1.0 M HCl (2 x 30 mL), H₂O (25 mL); Na2SO4 dried, and concentrated. The resulting residue is chromatographed to give the title compound (1.32 g, 2.09 mmol, 80%). ¹H NMR (CDCl₃), δ 0.06 (s, 3H), 0.12 (s, 3H), 0.69 (t, J = 7.1 Hz, 6H), 0.91 (s, 9H), 0.97 (s, 9H), 2.00-2.05 (m, 4H), 2.06 (s, 3H), 2.07 (s, 1.11 H), 2.10 (s, 1.89 H), 2.21 (s, 1.89 H), 2.24 (s, 1.11 H), 3.66-3.71 (m, 4H), 3.83-3.89 (m, 1H), 3.95 (s, 0.74 H), 3.96-4.01 (m, 1H), 4.04 (1.26 H), 4.60 (1.26H), 4.68 (0.74H), 6.49 (s, 0.37H), 6.51 (s, 0.63H), 6.65-6.69 (m, 1H), 6.97-7.03 (m, 2H). LC/MS (m/z): calcd for C₃₅H₅₈NO₅SSi (M+H)⁺: 632.4; found: 632.3.

E. 2-[N-Acetyl-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophen-2-ylmethyl)-amino]-acetic acid.

[0437] 

[0438] Using a procedure analogous to Example 124D, 2-{N-Acetyl-[5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl} -1-ethyl-propyl)-3-methyl-thiophen-2-ylmethyl]-aminol}-acetic acid methyl ester (1.32 g, 2.09 mmol) gives the title compound (0.95 g, 1.83 mmol, 88%). ¹H NMR (CD3OD), δ 0.72 (t, J = 7.3 Hz, 3H), 0.73 (t, J = 7.3 Hz, 3H), 1.05 (s, 9H), 2.03 (s, 3H), 2.05-2.14 (m, 4H), 2.16 (s, 1.5H), 2.18 (s, 1.5 H), 2.22 (s, 1.5 H), 2.24 (s, 1.5 H), 3.66 (dd, J = 7.6, 2.7 Hz, 1H), 3.91 (dd, J = 10.1, 7.6 Hz, 1H), 3.98 (s, 1H), 4.03 (s, 1H), 4.16 (dd, J = 10.1, 2.7 Hz, 1H), 4.67 (s, 1H), 4.71 (s, 1H), 6.59 (s, 0.5H), 6.63 (s, 0.5H), 6.80 (d, J = 3.1 Hz, 0.5H), 6.82 (d, J = 2.7 Hz, 0.5H), 7.01-7.10 (m, 2H). LC/MS (m/z): calcd for C₂₈H₄₀NO₅SSi (M-H)^-: 502.7; found: 502.2.

Example 131 and 132

Preparation of enantiomers of 2-[N-Acetyl-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methy]-phenyl]-propyl}-3-methyl-thiophen-2-ylmethyl)-amino]-acetic acid.

[0439] 

Enantiomer 2

[0440] A racemic mixture of 2-[N-acetyl-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophen-2-ylmethyl)-amino]-acetic acid (560 mg) is chromatographed (CHIRALPAK AD, 0.1 % TFA in i-PrOH/MeOH/Hept (20/5/75),) to give fraction-1 (338 mg, rt = 6.4 m), and fraction- 2, (343 mg, rt = 13.7 m). Fraction-1 is chromatographed to give the low Rf component (TLC: (EtOAc/CH₃OH/HOAc, 85/15/0.5; Rf= 0.5). The low Rf component is dissolved in CH₃OH (5mL), treated with 0.5 M NaOCH₃ (1.2 ml, 0.59 mmol), and stirred at RT for 10 m. The reaction is concentrated and partitioned between 1.0 M MCl (2 ml)/H₂O (10 ml)/EtOAc (3 x 15 ml). The organic layer is MgSO₄ dried and concentrated to give the enantiomer 1 of the title compound (Example 131) (153.7 mg, 27%).
Fraction-2 from the chiral resolution is manipulated as described for fraction-1 to give the enantiomer 2 of the title compound (Example 132) (149.9 mg, 27%).
Example 131, Enantiomer I CHIRALPAK AD, 0.1% TFA in i-PrOH/MeOH/Hept
(20/5/75); rt = 6.4 m.
NMR & LC/MS: identical to the racemic material, Example 130.
Example 132, Enantiomer 2 CHIRALPAK AD, 0.1% TFA in i-PrOH/MeOH/Hept
(20/5/75); rt =13.7 m.
NMR & LC/MS: Identical to the racemic material, Example 130.

Example 134

Preparation of (5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester.

[0441] 

A. 1-{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one.

[0442] 

[0443] A mixture of 3'-[4-(hydroxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane (4.4 g, 16.4 mmol), 1-chloro-3,3-dimethyl-butan-2-one (2.37 ml, 18.1 mmol) and K₂CO₃ (3.39 g, 24.6 mmol) in acetone (40 ml) is refluxed overnight. After cooling, the reaction is filtered, concentrated and partitioned between EtOAc and 1N HCl. The organic phase is Na2SO4 dried and concentrated to give the title compound (6.2 g, quantitative).
¹H NMR (CDCl₃): δ 7.05 (d, 1H, J = 1.2 Hz), 7.02 (dd, 1H, J = 8.8, 2.4 Hz), 6.70 (s, 1H), 6.60 (d, 1H, J = 1.2 Hz), 6.52 (d, 1H, J = 8.8 Hz), 4.84 (s, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 2.09 (q, 4H), 1.27 (s, 9H), 0.70 (t, 6H).

B. 1-{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol

[0444] 

[0445] To a stirred solution of 1-{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (5.2 g, 14 mmol) in THF/MeOH (40 ml/10 ml) at 0 °C is added NaBH₄ (528 mg, 14 mmol), warmed to RT, and stirred for 1h. The reaction is concentrated and the residue is partitioned between EtOAc and 0.2 N HCl. The organic layer is MgSO₄ dried and concentrated to give the title compound (5.4 g, quantitative).
¹H NMR (CDCl₃): δ 7.05 (s, 2H), 6.73 (s, 1H), 6.70 (s, 1H), 6.60 (s, 1H), 4.09 (dd, 1H, J = 8.1, 2.4 Hz), 3.87 (dd, 1H, J = 8.1, 8.9 Hz), 3.70 (dd, 1H, J = 8.9, 2.4 Hz), 2.20 (s, 6H), 2.07 (q, 4H), 1.01 (s, 9H), 0.70 (t, 6H);
ES-MS: 375 (M+1).

C. 1-{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-2-(t-butyldimethylsilyloxy)-3,3-dimethyl-butane.

[0446] 

[0447] To a solution of 1- {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol (7.5 g, 20 mmol) in dichloromethane (100 ml) at -78 °C is added 2,6-dimethylpyridine (5.8 ml, 50 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (6.0 ml, 26 mmol). After stirring at RT for 2 h, the reaction diluted with dichloromethane and washed successively with 1N HCl followed by satd NaHCO₃. The organic layer is dried over MgSO₄ and concentrated to give the title product (9.5 g, 97%).
¹H NMR (CDCl₃): δ 7.02, 7.06 (m, 2H), 6.61, 6.71 (m, 3H), 3.98 (dd, 1H, J = 3.5, 9.9 Hz), 3.84 (dd, 1H, J = 5.8, 9.9 Hz), 3.66 (dd, 1H, J = 3.5, 5.8 Hz), 2.20 (s, 3H), 2.19 (s, 3H), 2.08 (q, 4H), 0.96 (s, 9H), 0.90 (s, 9H), 0.70 (t, 6H), 0.10 (s, 3H), 0.05 (s, 3H).

D. 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonyl chloride.

[0448] 

[0449] Add n-BuLi (6 ml, 9.6 mmol, 1.6 M/Hex) to a solution of 1-{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-2-(t-butyldimethylsilyloxy)-3,3-dimethyl-butane (3.9 g, 8 mmol) in THF (20 ml) at 0 °C. After 1h, the mixture is transferred through cannula into a solution of SO₂Cl₂ (0.65 ml, 8 mmol) in pentane (30 ml) at -78°C. It is stirred at RT for 2 h and concentrated. The residue is dissolved in dichloromethane (20 ml) and used for the next reaction without further purification.

E. [5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonylamine]-acetic acid methyl ester.

[0450] 

[0451] An aliquot of 5-(1-(4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl)-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonyl chloride (step D) (4 ml, 1.5 mmol) is added to a suspension of glycine methyl ester hydrochloride (565 mg, 4.5 mmol) and Et₃N (0.94 ml, 6.75 mmol) in dichloromethane (10 ml) at 0 °C. It is stirred at RT overnight, concentrated, and partitioned between EtOAc and 1N HCl. The organic layer is concentrated and chromatographed (Hex to 20% EtOAc/Hex) to give the title product (3 80 mg, 40%).
¹H NMR (CDCl₃): δ 7.01 (dd, 1H, J = 2.0, 8.3 Hz), 6.97 (d, 1H, J = 2.0 Hz), 6.68 (d, 1H, J = 8.3 Hz), 6.59 (s, 1H), 5.10 (t, 1H), 3.98 (dd, 1H, J = 3.5, 9.9 Hz), 3.84, 3.88 (m, 3H), 3.65, 3.69 (m, 4H), 2.41 (s, 3H), 2.20 (s, 3H), 2.09 (q, 4H), 0.97 (s, 9H), 0.90 (s, 9H), 0.70 (t, 6H), 0.11 (s, 3H), 0.05 (s, 3H);
ES-MS: 640 (M+1).

F. (5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester.

[0452] 

[0453] To a solution of [5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonylamine]-acetic acid methyl ester (380 mg, 0.59 mmol) in acetonitrile (10 ml) at 0 °C is added hydrofluoride solution (3 ml, 48% in water). After stirring at RT for 2 h, the reaction is concentrated and partitioned between EtOAc and 1N HCl. The organic layer is washed successively with 1N HCl and brine. The organic layer is concentrated and chromatographed (Hex to 25% EtOAc/Hex) to give the title compound (250 mg, 82%). ¹H NMR (EDCl₃): δ 7.02 (dd, 1H, J = 2.5, 8.3 Hz), 6.97 (d, 1H, J = 2.0 Hz), 6.73 (d, 1H, J = 8.3 Hz), 6.58 (s, 1H), 5.12 (t, 1H), 4.10 (dd, 1H, J = 2.5, 8.6 Hz), 3.87 (dd, 1H, J = 8.6, 8.8 Hz), 3.84 (d, 2H, J = 5.3 Hz), 3.71 (dd, 1H, J = 2.5,8.8 Hz), 3.66 (s, 3H), 2.40 (s, 3H), 2.20 (s, 3H), 2.07 (q, 4H), 1.02 (s, 9H), 0.69 (t, 6H);
HRMS: Calcd. for C26H43N2O6S2 (M+18), 543.2563, found, 543.2550.

Example 135 and Example 136

Preparation of enantiomers of (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester.

[0454] 

[0455] A racemic mixture of (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester (750 mg) is chromatographed on Chiralpak AD column to give enantiomer 1, Example 135 (400 mg, 53%) and enantiomer 2, Example 136 (320 mg, 43%).
HPLC: Chiralpak AD (4.6 x 150 mm); 35% heptane, 65% EtOH; flow rate: 0.6 ml/m; UV: 260 nm
Enantiomer 1, Example 135: rt = 4.5 m;
¹H NMR (CDCl₃): equivalent to Example 134
Enantiomer 2, equivalent to Example 136: rt = 5.6 m.
¹H NMR (CDCl₃): equivalent to Example 134

Example 137

Preparation of (5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetac acid.

[0456] 

[0457] To a solution of (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester (210 mg, 0.4 mmol) in dioxane (10 ml) is added 2N LiOH/H₂O solution (10 ml) and stirred at RT overnight. The reaction is concentrated and partitioned between EtOAc/1N HCl. The organic layer is concentrated to give the title compound (180 mg, 88%).
¹H NMR (CDCl₃): δ 7.01 (dd, 1H, J = 2.5, 8.3 Hz), 6.97 (d, 1H, J = 2.0 Hz), 6.73 (d, 1H, J = 8.3 Hz), 6.60 (s, 1H), 5.16 (t, 1H), 4.12 (dd, 1H, J = 2.9, 9.3 Hz), 3.88 (dd, 1H, J = 8.8, 9.3 Hz), 3.86(d, 2H, J = 5.5 Hz), 3.72 (dd, 1H, J = 2.9, 8.8 Hz), 2.40 (s, 3H), 2.20 (s, 3H), 2.05 (q, 4H), 1.01 (s, 9H), 0.70 (t, 6H);
HRMS: Calcd. for C25H38NO6S2 (M+1), 512.2146, found, 512.2141.

Example 138

Preparation of enantiomers of (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid.

[0458] 

[0459] Using a procedure analogous to Example 136, enantiomer 1 of (5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester (390 mg, 0.74 mmol) (Example 135) gives the title compound (250 mg, 66%).
¹H NMR (CDCl₃): equivalent to Example 134;
ES-MS: 512 (M+1).

Example 139

Preparation of (5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid.

[0460] 

A. [5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonylamine]-acetic acid tert-butyl ester.

[0461] 

[0462] Using a procedure analogous to Example 134E, 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonyl chloride and 2-amino-acetic acid tert-butyl ester (787 mg, 6 mmol) give the title compound (670 mg, 20%).
¹H NMR (CDCl₃): δ 7.01 (dd, 1H, J = 2.5, 8.8 Hz), 6.97 (d, 1H, J = 2.0 Hz), 6.68 (d, 1H, J = 8.8 Hz), 6.57 (s, 1H), 5.09 (t, 1H), 3.98 (dd, 1H, J = 3.5, 9.8 Hz), 3.86 (dd, 1H, J = 5.9, 9.8 Hz), 3.71 (d, 2H, J = 5.4 Hz), 3.67 (dd, 1H, J = 3.5, 5.9 Hz), 2.40 (s, 3H), 2.20 (s, 3H), 2.08 (q, 4H), 1.40 (s, 9H), 0.97 (s, 9H), 0.90 (s, 9H), 0.70 (t, 6H), 0.11 (s, 3H), 0.05 (s, 3H).

B. (5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid tert-butyl ester.

[0463] 

[0464] A mixture of [5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonylamine]-acetic acid tert-butyl ester (667 mg, 1 mmol) and tetra-n-butylammonium fluoride (6 ml, 1M in THF) is stirred at RT for 3 d. It is diluted with EtOAc and washed with NH₄Cl. The organic layer is concentrated and chromatographed (Hex to 15% EtOAc/Hex) to give the title compound (360 mg, 63%).
ES-MS: 568 (M+1).

C. (5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid tert-butyl ester.

[0465] 

[0466] A mixture of (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid tert-butyl ester (360 mg, 0.63 mmol), pyridinium dichromate (179 mg, 0.48 mmol) and Ac₂O (66 µL, 0.7 mmol) in dichloromethane (10 ml) is refluxed for 3 h. The reaction is concentrated and chromatographed (Hex to 15% EtOAc/Hex) to give the title compound (330 mg, 92%);
¹H NMR (CDCl₃): δ 6.96, 7.23 (m, 2H), 6.56 (s, 1H), 6.51 (d, 1H, J = 8.3 Hz), 6.57 (s, 1H), 5.08 (t, 1H), 4.85 (s, 2H), 3.71 (d, 2H, J = 5.4 Hz), 2.40 (s, 3H), 2.26 (s, 3H), 2.07 (q, 4H), 1.40 (s, 9H), 1.26 (s, 9H), 0.90 (s, 9H), 0.70 (t, 6H);
HRMS: calcd. for C29H47N2O6S2 (M+18), 583.2876, found, 583.2876.

D. (5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid.

[0467] 

[0468] A solution of (5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid tert-butyl ester (320 mg, 0.57 mmol) in 4N HCl/dioxane (10 ml) is stirred at RT overnight. The reaction is concentrated and chromatographed (Hex to 0.5% AcOH in 50% EtOAc/Hex) to give the title compound (250 mg, 87%).
¹H NMR (EDCl₃): δ 7.01 (d, 1H, J = 2.5 Hz), 6.92 (dd, 1H, J = 2.5, 8.8 Hz), 6.62 (s, 1H), 6.45 (d, 1H, J = 8.8 Hz), 5.10 (t, 1H), 4.91 (s, 2H), 3.86(d, 2H, J = 5.4 Hz), 2.41 (s, 3H), 2.25 (s, 3H), 2.04 (q, 4H), 1.25 (s, 9H), 0.71 (t, 6H);
HRMS: Calcd. for C25H39N2O6S2 (M+18), 527.2250, found, 527.2245.

Example 140

Preparation of 3-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid ethyl ester.

[0469] 

[0470] Using procedures analogous to Example 134E and Example 134F, an aliquot of 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonyl chloride (Example 134D) and 3-amino-propionic acid ethyl ester hydrochloride give the title compound (19% overall yield).
¹H NMR (CDCl₃): δ 7.02 (dd, 1H, J = 2.5, 8.8 Hz), 6.98 (d, 1H, J = 2.0 Hz), 6.73 (d, 1H, J = 8.8 Hz), 6.58 (s, 1H), 5.26 (t, 1H), 4.14 (q, 2H), 4.10 (dd, 1H, J = 2.9, 8.9 Hz), 3.87 (dd, 1H, J = 8.8, 8.9 Hz), 3.71 (dd, 1H, J = 2.9, 8.8 Hz), 3.25 (m, 2H), 2.50 (t, 2H), 2.39 (s, 3H), 2.20 (s, 3H), 2.06 (q, 4H), 1.02 (s, 9H), 0.70 (t, 6H);
HRMS: Calcd. for C28H44NO6S2 (M+1), 554.2610, found, 554.2590.

Example 141

Preparation of 3-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid.

[0471] 

[0472] The title compound is obtained from 3-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid ethyl ester using an analogous procedure as described for Example 137.
¹H NMR (CDCl₃): δ 7.02 (d, 1H, J = 8.3 Hz), 6.98 (s, 1H), 6.73 (d, 1H, J = 8.3 Hz), 6.60 (s, 1H), 5.50 (t, 1H), 4.13 (d, I H), 4.12 (dd, 1H, J = 2.0, 8.9 Hz), 3.88 (dd, 1H, J = 8.8, 8.9 Hz), 3.72 (dd, 1H, J = 2.0, 8.8 Hz), 3.26 (m, 2H), 2.55 (t, 2H), 2.39 (s, 3H), 2.20 (s, 3H), 2.06 (q, 4H), 1.02 (s, 9H), 0.70 (t, 6H);
HRMS: Calcd. for C26H40NO6S2 (M+1), 526.2297, found, 526.2275.

Example 142 and Example 143

Preparation of enantiomers of 3-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propy}-3-methyl-thiopbene-2-sulfonylamine)-propionic acid.

[0473] 

[0474] A racemic mixture of 3-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid (200 mg) is chromatographed on a Chiralpak AD column to give enantiomer 1, example 142 (79 mg, 40%) and enantiomer 2, Example 143 (79 mg, 40%).
HPLC: Chiralpak AD (4.6 x 250 mm); 0.1% TFA in 15% EtOH/85% Hept; flow rate: 1.0 ml/m; UV: 260 nm
Enantiomer 1: rt = 12 m;
¹H NMR (CDCl₃): equivalent to Example 141;
ES-MS: 526 (M+1)
Enantiomer 2: rt = 21 m;
¹H NMR (CDCl₃): equivalent to Example 141;
ES-MS: 526 (M+1).

Example 144

Preparation of 3-(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid.

[0475] 

[0476] The title compound is obtained from 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonyl chloride and 2-amino-acetic acid tert-butyl ester and 3-amino-propionic acid t-butyl ester hydrochloride using an analogous procedures as described for Example 139A to Example 139D.
¹H NMR (CDCl₃): δ 6.99.(s, 1H), 6.97 (d, 1H, J = 8.4 Hz), 6.59 (s, 1H), 6.50 (d, 1H, J = 8.4 Hz), 5.61 (t, 1H), 4.87 (s, 2H), 3.26 (m, 2H), 2.55 (t, 2H), 2.39 (s, 3H), 2.25 (s, 3H), 2.06 (q, 4H), 1.26 (s, 9H), 0.69 (t, 6H);
ES-MS: 524 (M+1).

Example 145

Preparation of 3-[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonyl)-methyl-amine]-propionic acid.

[0477] 

A. 3-[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonyl)-methyl-amine]-propionic acid tert-butyl ester.

[0478] 

[0479] To a mixture of 3-(5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid tert-butyl ester (Example 143C) (400 mg, 0.69 mmol) and THF (15 ml) is added PPh₃ (272 mg, 1.04 mmol), diethyl azodicarboxylate (163 µL, 1.04 mmol) and methanol (42 µL, 1.04 mmol). The reaction is stirred at RT overnight, concentrated and chromatographed (Hex to 20% EtOAc/Hex) to give the title compound (240 mg, 59%).
¹H NMR (EDCl₃): δ 6.99 (s, 1H), 6.97 (d, 1H, J = 8.4 Hz), 6.57 (s, 1H), 6.52 (d, 1H, J = 8.4 Hz), 4.85 (s, 2H), 3.37 (t, 2H), 2.81 (s, 3H), 2.51 (t, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 2.06 (q, 4H), 1.44 (s, 9H), 1.26 (s, 9H), 0.69 (t, 6H).

B. 3-[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonyl)-methyl-amine]-propionic acid.

[0480] 

[0481] The title compound is prepared from 3-[(5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonyl)-methyl-amine]-propionic acid tert-butyl ester using a procedure analogous to Example 139D.
¹H NMR (CDCl₃): δ 6.99 (s, 1H), 6.97 (d, 1H, J = 8.4Hz), 6.60 (s, 1H), 6.50 (d, 1H, J = 8.4 Hz), 4.87 (s, 2H), 3.4] (t, 2H), 2.84 (s, 3H), 2.63 (t, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 2.06 (q, 4H), 1.26 (s, 9H), 0.69 (t, 6H).
HRMS: calcd. for C27H40NO6S2, 538.2297, found, 538.2296.

Example 146

2-(R)-(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid.

[0482] 

[0483] The title compound is prepared from 2-(R)-amino-propionic acid tert-butyl ester hydrochloride following an analogous procedure as described for Example 139.
¹H NMR (CDCl₃): δ 6.96 (d, 1 H, J = 2.5 Hz), 6.97 (dd, 1H, J = 2.0, 8.8 Hz), 6.61 (s, 1H), 6.44 (d, 1H, J = 8.5 Hz), 5.26 (d, 1H, J = 8.3 Hz), 4.92 (s, 2H), 4.11 (m, 1H), 2.40 (s, 3H), 2.25 (s, 3H), 2.06 (q, 4H), 1.42 (d, 3H, J = 7.4 Hz), 1.25 (s, 9H), 0.69 (t, 6H);
ES-MS: 524 (M+1).

Example 147

2-(R)-(5-{1-[4-(3,3-Dimethyl-2-thioxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid.

[0484] 

[0485] A mixture of 2-(R)-(5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid (125 mg, 0.2 mmol) and Lawesson's reagent (236 mg, 0.5 mmol) in dichloroethane (7 ml) is refluxed for 3 d. The solvent is concentrated and chromatographed (0.1% AcOH in 50% EtOAc/Hex) to give the title compound (67 mg, 52%).
¹H NMR (CDCl₃): δ 6.97 (s, 1H), 6.96 (d, 1H, J = 8.4 Hz), 6.60 (s, 1H), 6.50 (d, 1H, J = 8.4 Hz), 5.19 (d, 1H, J = 8.8 Hz), 4.86 (s, 2H), 4.14 (m, 1H), 2.40 (s, 3H), 2.25 (s, 3H), 2.06 (m, 4H), 1.38 (d, 3H), 1.26 (s, 9H), 0.69 (t, 6H);
HRMS: calcd. for C36H38NO5S3, 540.1912, found, 540.1908.

Example 148

Preparation of 2-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-2-methyl-propionic acid methyl ester.

[0486] 

[0487] Using analogous procedures as described for Example 134D to Example 134F, 2-amino-2-methyl-propionic acid methyl ester hydrochloride gives the title compound (20% overall yield).
¹H NMR (CDCl₃): δ 7.03 (dd, 1H, J = 2.4, 8.4 Hz), 6.96 (d, 1H, J = 2.3 Hz), 6.72 (d, 1H, J = 8.8 Hz), 6.53 (s, 1H), 5.42 (s, 1H), 4.10 (dd, 1H, J = 2.6, 9.2 Hz), 3.87 (dd, 1H, J = 8.8, 9.2 Hz), 3.69 (dd, 1H, J = 2.6, 8.8 Hz), 3.67 (s, 3H), 2.38 (s, 3H), 2.19 (s, 3H), 2.06 (q, 4H), 1.48 (s, 6H), 1.02 (s, 9H), 0.69 (t, 6H);
HRMS: Calcd. for C28H44NO6S2 (M+1), 554.2610, found, 554.2610.

Example 149

Preparation of 2-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-benzoic acid.

[0488] 

[0489] Using analogous procedures as described for Example 134D to Example 134F and Example 137, 2-amino-benzoic acid methyl ester gives the title compound (8% overall yield).
¹NMR (400MHz, CDCl₃) δ 10.54 (s, 1H), 8.03 (d, 1H, J=7.9 Hz), 7.71 (d, 1H, J=8.4 Hz), 7.48 (t, 1H, =7.9 Hz), 7.09 (t, 1H, J=7.7 Hz), 6.93 (dd, 1H, J=8.6, 2.4 Hz), 6.86 (s, 1H), 6.70 (d, 1H, J=8.4 Hz), 6.48 (s, 1H), 4.14-4.07 (m, 1H), 3.89 (t, 1H, J=9.0 Hz), 3.72 (dd, 1H, J=8.6, 2.4 Hz), 2.30 (s, 3H), 2.16 (s, 3H), 2.04-1.93 (m, 4H), 1.02 (s, 9H), 0.60 (t, 6H, J=7.3 Hz).
High Res. EI-MS: 574.2305; calc. for C₃₀H₃₉NO₆S₂+H: 574.2297

Example 150

Preparation of epimer 1 of 2-(R)-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid methyl ester.

[0490] 

A. Enantiomer 1 of 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol.

[0491] 

[0492] To a mixture of (R)-2-methyl-CBS-oxazaborolidine (0.1 ml, 0.1 mmol, 1 M in toluene), borane-N, N-dimethyl aniline complex (0.18 ml, 1 mmol) in THF (5 ml) is added a solution of 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (372 mg, 1 mmol) in THF (5 ml) over a period of 40 m. The reaction is stirred at RT for 2 h and MeOH (2 ml) is added followed by 1N hydrochloric acid. The mixture is extracted with EtOAc and the organic phase is concentrated and chromatographed (Hex to 25% EtOAc/Hex) to give the title compound (305 mg, 82%).
HPLC: Chiralpak AD (0.46 x 25 cm); 20% 2-propanol, 80% heptane; flow rate: 1.0 ml/m; UV: 225 nm;
Enantiomer 1: 91% ee; rt: 4.03 m.
¹H NMR (CDCl₃) equivalent to Example 134B

B. Epimer 1 of 2-(R)-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-propionic acid methyl ester

[0493] 

[0494] Using analogous procedures described in Example 134C to Example 134F, enantiomer 1 of 1-{4-[1-methyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol and 2-(R)-amino-propionic acid methyl ester hydrochloride give the title compound (27% overall yield).
¹NMR (400MHz, CDCl₃) δ 7.01 (d, 1H; J=8.4 Hz), 6.96 (s, 1H), 6.72 (d, 1H, J=8.4 Hz), 6.56 (s, 1H), 5.26 (d, 1H, J=8.8 Hz), 4.10-4.03 (m, 2H), 3.86 (t, 1H, J=9.0 Hz), 3.71 (dd, JH, J=8.8, 2.2 Hz), 3.59 (s, 3H), 2.38 (s, 3H), 2.19 (s, 3H), 2.11-2.03 (m, 4H), 1.38 (d, 3H, J=7.0 Hz), 1.01 (s, 9H), 0.68 (t, 6H, J=7.3 Hz).
High Res. EI-MS: 540.24556; calc. for C₂₇H₄₁NO₆S₂+H: 540.2454

Example 152

Preparation of enantiomer 1 of (5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-thiophene-2-sulfonylamine)-acetic acid methyl ester.

[0495] 

[0496] Using a procedure analogous to Example 150A, 1-[4-(1-ethyl-1-thiophen-2-yl-propyl)-2-methyl-phenoxy]-3,3-dimethyl-butan-2-one gives the title compound (18%).
¹H NMR (CDCl₃) δ 7.43 (d, 1H, J = 4.0 Hz), 7.02 (dd, 1H, J = 2.0, 8.5 Hz), 6.98 (s, 1H), 6.74 (s, 1H), 6.73 (d, 1H, J = 8.8 Hz), 5.11 (t, 1H), 4.10 (dd, 1H, J = 2.6, 9.2 Hz), 3.88 (dd, 1H, J = 8.8, 9.2 Hz), 3.85 (d, 2H, J = 4.8 Hz), 3.71 (dd, 1H, J = 2.6, 8.8 Hz), 3.66 (s, 3H), 2.19 (s, 3H), 2.07 (m, 4H), 1.01 (s, 9H), 0.70 (t, 6H);
HRMS: Calcd, for C25H41N2O6S2 (M+18), 529.2406, found, 529.2413.

Example 153

Preparation of enantiomer 1 of (5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-thiophene-2-sulfonylamine)-acetic acid.

[0497] 

[0498] Using an analogous precedure to Example 137, enantiomer 1 of (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-thiophene-2-sulfonylamine)-acetic acid methyl ester give the title compound (quant).
¹H NMR (CDCl₃) δ 7.44 (d, 1H, J = 4.0 Hz), 7.0 (d, 1H, J = 8.4 Hz), 6.98 (s, 1H), 6.78 (d, 1H, J = 4.0 Hz), 6.74 (d, 1H, J = 8.4 Hz), 5.11 (t, 1H), 4.10 (dd, 1H, J= 2.5, 9.2 Hz), 3.88 (dd, 1H, J = 8.8, 9.2 Hz), 3.85 (d, 2H, J = 4.4 Hz), 3.71 (dd, 1H, J = 2.5, 8.8 Hz), 2.19 (s, 3H), 2.07 (m, 4H), 1.01 (s, 9H), 0.70 (t, 6H);
HRMS: Calcd. for C24H39N2O6S2 (M+18), 515.2249, found, 515.2267.

Example 154

Preparation of enantiomer 1 of (5-{1-ethyl-1-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-butoxy)-phenyl]-propyl}-thiophene-2-sulfonylamine)-acetic acid methyl ester.

[0499] 

[0500] Using a procedure analogous to Example 150A, 1-[2-ethyl-4-(1-ethyl-1-thiophen-2-yl-propyl)-phenoxy]-3,3-dimethyl-butan-2-one gives the title compound (34%).
¹H NMR (CDCl₃) δ 7.43 (d, 1H, J = 3.5 Hz), 7.02 (d, 1H, J = 8.3 Hz), 7.00 (s, 1H), 6.76 (d, 1H, J = 3.5 Hz), 6.75 (d, 1H, J = 8.3 Hz), 5.06 (t, 1H), 4.10 (dd, 1H, J = 2.6, 9.3 Hz, 3.88 (dd, 1H, J = 8.8, 9.3 Hz), 3.85 (d, 2H, J = 5.8 Hz), 3.71 (dd, 1H, J = 2.6, 8.8 Hz), 3.67 (s, 3H), 2.60 (q, 2H), 2.06 (q, 4H), 1.14 (t, 3H), 1.01 (s, 9H), 0.70 (t, 6H);
HRMS: Calcd, for C26H40NO6S2 (M+1), 526.2297, found, 526.2285.

Example 155

Preparation of enantiomer 1 of (5-{1-Ethyl-1-[3-ethyl-4-(2-hydroxy-3,3-dimethyl-butoxy)-phenyl]-propyl}-thiophene-2-sulfonylamine)-acetic acid.

[0501] 

[0502] Using a procedure analogous to Example 137, enantiomer 1 of (5-{1-ethyl-[3 ethyl-4-(2-hydroxy-3,3-dimethyl-butoxy)-phenyl]-propyl}-thiophene-2-sulfonylamine)-acetic acid methyl ester gives the title compound (quant).
¹H NMR (EDCl₃) δ 7.44 (d, 1H, J=4.0 Hz), 6.98, 7.01 (m, 2H), 6.74, 6.79 (m, 2H), 5.11 (t, I H), 4.13 (dd, 1H, J = 3.0, 9.4 Hz), 3.90 (dd, 1H, J = 8.9, 9.4 Hz), 3.86 (d, 2H, J = 5.3 Hz), 3.73 (dd, 1H, J = 3.0, 8.9 Hz), 2.60 (q, 2H), 2.09 (m, 4H), 1.16 (t, 3H), 1.03 (s, 9H), 0.72 (t, 6H);
HRMS: Calcd. for C25H41N2O6S2 (M+18), 529.2406, found, 529.2397.

Example 156

Preparation of enantiomer 1 of (5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-propyl-phenyl]-propyl}-thiophene-2-sulfonylamine)-acetic acid methyl ester.

[0503] 

[0504] Using a procedure analogous to Example 150, 1-[4-(1-ethyl-1-thiophen-2-yl-propyl)-2-propyl-phenoxy]-3,3-dimethyl-butan-2-one gives the title compound (25%).
¹H NMR (CDCl₃) δ 7.43 (d, 1H, J = 4.0 Hz), 7.02 (dd, 1H, J = 1.8, 8.8 Hz), 7.00 (d, 1H, J = 1.8 Hz), 6.77 (d, 1H, J=4.0 Hz), 6.75 (d, 1H, J = 8.8 Hz), 5.05 (t, 1H), 4.10 (dd, 1H, J = 2.4, 8.8 Hz), 3.88 (dd, 1H, J = 8.8, 9.2 Hz), 3.85 (d, 2H, J = 5.2 Hz), 3.71 (dd, 1H, J = 2.4, 8.8 Hz), 3.67 (s, 3H), 2.55 (t, 2H), 2.06 (q, 4H), 1.56 (m, 2H), 1.02 (s, 9H), 0.89 (t, 3H), 0.70 (t, 6H);
HRMS: Calcd. for C27H45N2O6S2 (M+18), 557.2719, found, 557.2698.

Example 157

Preparation of (5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-propyl-phenyl]-propyl}-thiophene-2-sulfonylamine)-acetic acid.

[0505] 

[0506] Using a procedure analogous to Example 137, (5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-propyl-phenyl]-propyl}-thiophene-2-sulfonylamine)-acetic acid methyl ester gives the title compound (quant).
¹H NMR (CDCl₃) δ 7.43 (d, 1H, J = 4.0 Hz), 6.99 (d, 1H, J = 8.4 Hz), 6.98 (s, 1H), 6.78 (d, 1H, J = 4.0 Hz), 6.75 (d, 1H, J = 8.4 Hz), 5.09 (t, 1H), 4.10 (dd, 1H, J = 2.4, 9.4 Hz), 3.88 (dd, 1H, J = 8.8, 9.4 Hz), 3.86 (d, 2H, J = 5.3 Hz), 3.72 (dd, 1H, J = 2.4, 8.8 Hz), 2.55 (t, 2H), 2.07 (m, 4H), 1.56 (m, 2H), 1.01 (s, 9H), 0.89 (t, 3H), 0.71 (t, 6H);
HRMS: Calcd. for C26H43N2O6S2 (M+18), 543.2563, found, 543.2541.

Example 158

Preparation of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonic acid acetyl-amide

[0507] 

A. 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonic acid amide

[0508] 

[0509] Using a procedure analogous to Example 134E, 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-metbyl-thiophene-2-sulfonyl chloride and NH₄OH give the title compound (39%).
¹H NMR (CDCl₃) δ 7.02 (dd, 1H, J = 2.9, 8.6 Hz), 6.96 (d, 1H, J = 2.2 Hz), 6.68 (d, 1H, J = 8.6 Hz), 6.60 (s, 1H), 4.83 (s, 2H), 3.98 (dd, 1H, J = 3.3, 9.9 Hz), 3.85 (dd, 1H, J = 5.5, 9.9 Hz), 3.67 (dd, 1H, J = 3.3, 5.5 Hz), 2.43 (s, 3H), 2.20 (s, 3H), 2.06 (q, 4H), 0.96 (s, 9H), 0.89 (s, 9H), 0.70 (t, 6H), 0.11 (s, 3H), 0.05 (s, 3H).

B. 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonic acid acetyl-amide.

[0510] 

[0511] A mixture of 5-(1-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonic acid amide (227 mg, 0.4 mmol), EDCI (92 mg, 0.48 mmol), acetic acid (27 µL, 0.48 mmol) and DMAP (50 mg) in dichloromethane (10 ml) is stirred at RT overnight. The reaction is diluted with dichloromethane and washed with 1N HCl. The organic phase is concentrated and chromatographed (Hex to 20% EtOAc/Hex) to give the title compound (240 mg, 98%).
¹H NMR (CDCl₃) δ 7.99 (s, 1H), 7.02 (d 1H, J = 8.8 Hz), 6.96 (s, 1H), 6.69 (d, 1H, J = 8.8 Hz), 6.59 (s, 1H), 3.98 (dd, 1H, J= 3.4, 9.8 Hz), 3.85 (dd, 1H, J = 5.8, 9.8 Hz), 3.67 (dd, 1H, J = 3.4, 5.8 Hz), 2.43 (s, 3H), 2.20 (s, 3H), 2.13 9s, 3H), 2.06 (q, 4H), 0.96 (s, 9H), 0.89 (s, 9H), 0.70 (t, 6H), 0.1,1 (s, 3H), 0.05 (s, 3H);
ES-MS: 610 (M+1).

C. 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonic acid acetyl-amide.

[0512] 

[0513] Using a procedure analogous to example-TWM-1F, 5-(1-{4-[2-(tert-butyldimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonic acid acetyl-amide gives the title compound (240 mg, 62%).
¹H NMR (CDCl₃) δ 7.97 (s, 1H), 7.02 (dd, 1H, J = 2.4, 8.3 Hz), 6.99 (s, I H), 6.74 (d, 1H, J = 8.3 Hz), 6.58 (s, 1H), 4.10 (dd, 1H, J = 2.4, 9.3 Hz), 3.88 (dd, 1H, J = 8.8, 9.3 Hz), 3.72 (dd, 1H,J= 2.4, 8.8 Hz), 2.46 (s, 3H), 2.21 (s, 3H), 2.13 (s, 3H), 2.07 (m, 4H), 1.02 (s, 9H), 0.70 (t, 6H).
HRMS: calcd. for C25H38NO5S2 (M+1), 496.2191, found, 496.2188.

Example 159

Preparation of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl}-propyl}-3-methyl-thiophene-2-sulfonic acid propionyl-amide.

[0514] 

[0515] Using procedures analogous to Example 158B and Example 158C, 5-(1-{4-[2-(tert-butyl-dimetyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonic acid amide and propionic acid give the title compound (66%).
¹H NMR (CDCl₃) δ 8.56 (s, 1H), 7.02 (dd, 1H, J =2.4, 8.3 Hz), 6.98 (d, 1H, J = 2.4 Hz), 6.73 (d, 1H, J = 8.3 Hz), 6.56 (s, 1H), 4.10 (dd, 1H, J = 3.0, 9.3 Hz), 3.88 (dd, 1H, J = 8.8, 9.3 Hz), 3.71 (dd, 1H, J = 3.0, 8.8 Hz), 2.47 (s, 3H), 2.33 (q, 2H), 2.19 (s, 3H), 2.07 (m, 4H), 1.08 (t, 3H), 1.02 (s, 9H), 0.68 (t, 6H);
HRMS: calcd. for C26H40NO5S2 (M+1), 510.2348, found, 510.2359.

Example 160

Preparation of 5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid acetyl-amide.

[0516] 

[0517] Using a procedure analogous to Example 138C, 5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonic acid acetyl-amide gives the title compound (84%).
¹H NMR (CDCl₃) δ 8.05 (s, 1H), 6.91, 6.99 (m, 2H), 6.57 (s, 1H), 6.51 (d, 1H, J = 8.5 Hz), 4.86 (s, 2H), 2.46 (s, 3H), 2.26 (s, 3H), 2.13 (s, 3H), 2.07 (m, 4H), 1.26 (s, 9H), 0.69 (t, 6H).
HRMS: calcd. for C25H36NO5S2 (M+1), 494.2035, found, 494.2040.

Example 161

Preparation of 5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid dimethylaminemethyleneamide.

[0518] 

A. 5-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide.

[0519] 

[0520] To a 0 °C solution of tert-butyl-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-dimethyl-silane (28.37 g, 72.99 mmol) in THF (360 ml) is added dropwise n-butyllithium (47.90 ml, 76.64 mmol, 1.6M in Hex) and stirred at 0 °C for 30 m. The reaction mixture is cannulated into a -78 °C solution of sulfuryl chloride (11.73 ml, 145.98 mmol) in pentane (360 ml) and the reaction warms to RT for 2 h. The reaction mixture is concentrated and the residue is dissolved in acetone (100 ml) and added to a 0 °C mixture of acetone (1 L) and concentrated NH₄OH (150 ml) and stirs at 0 °C for 2 h. The reaction mixture is concentrated and the residue is partitioned between EtOAc (700 ml) and satd aqueous NH₄Cl (200 ml). The organic layer is MgSO₄ dried, concentrated and chromatographed (330 g SiO₂, 50% EtOAc/Hex) to yield the title compound (5.34 g, 16%).
¹NMR (400MHz, CDCl₃) δ 6.97 (d, 1H, J=2.2 Hz), 6.91 (dd, 1H, J=8.6, 2.4 Hz), 6.66 (d, 1H, J=8.4 Hz), 6.58 (s, 1H), 4.90 (s, 2H), 2.42 (s, 3H), 2.17 (s, 3H), 2.09-2.04 (m, 4H), 1.00 (s, 9H), 0.69 (t, 6H, J=7.3 Hz), 0.21 (s, 6H).

B. 5-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid dimethylaminemethyleneamide.

[0521] 

[0522] To a solution of 5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide (5.34 g, 11.42 mmol) in THF (200 ml) is added dimethyl formamide dimethyl acetamide (1.52 ml, 11.42 mmol) and sitrred overnight. The reaction mixture is diluted with EtOAc (500 ml) and washed with 0.2N HC1 (100 ml). The organic layer is MgSO₄ dried, concentrated and chromatographed (120 g SiO₂, 50% EtOAc/Hex) to yield the title compound (6.0 g, quant.).
¹NMR (400MHz, CDCl₃) δ 8.10 (s, 1H), 6.98 (d, 1H, J=2.2 Hz), 6.92 (dd, 1H, J=8.4, 2.6 Hz), 6.65 (d, 1H, J=8.4 Hz), 6.52 (s, 1H), 3.12 (s, 3H), 3.05 (s, 3H), 2.41 (s, 3H), 2.16 (s, 3H), 2.09-1.99 (m, 4H), 1.00 (s, 9H), 0.68 (t, 6H, J=7.3 Hz), 0.20 (s, 6H).

C. 5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methylthiophene-2-sulfonic acid dimethylaminemethyleneamide

[0523] 

[0524] To a 0 °C solution of 5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid dimethylaminemethyleneamide (6.1 g, 11.68 mmol) in THF (150 ml) is added dropwise tetrabutylammonium fluoride (15.62 ml, 15.62 mmol, 1.0M in THF) and is warmed to RT for 1 h. The reaction is quenched with satd aqueous NH₄C1 (100 ml) and extracted with Et₂O (2 x 200 ml). The combined organic layers are dried MgSO₄ dried, concentrated and chromatographed (120 g SiO₂, 50% EtOAc/Hex) to yield the title compound (4.63 g, 97%).
¹NMR (400MHz, CDCl₃) δ 8.09 (s, 1H), 6.97 (s, 1H), 6.95 (d, 1H, J=8.4 Hz), 6.68 (d, 1H, J=8.4 Hz), 6.52 (s, 1H), 4.84 (s, 1H), 3.12 (s, 3H), 3.04 (s, 3H), 2.40 (s, 3H), 2.21 (s, 3H), 2.08-2.01 (m, 4H), 0.68 (t, 6H, J=7.3 Hz).

D. 5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid dimethylaminemethyleneamide.

[0525] 

[0526] To a solution of 5-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophene-2-sulfonic acid dimethylaminemethyleneamide (5.1 g, 12.48 mmol) in 2-butanone (50 ml) is added potassium carbonate (2.59 g, 18.72 mmol), and chloropinacolone (3.28 ml, 24.91 mmol). The reaction is refluxed overnight, filtered, and concentrated. The residue is partitioned between EtOAc (400 ml) and 0.2N HC1 (100 ml). The organic layer is washed with brine (100 ml), MgSO₄ dried, concentrated, and chromatographed (120 g SiO₂, 50% EtOAc/Hex) to yield the title compound (6.11 g, 97%).
¹NMR (400MHz, CDCl₃) δ 8.10 (s, 1H), 7.01 (s, 1H), 6.98 (d, 1H, J=9.2 Hz), 6.52 (s, 1H), 6.50 (d, 1H, J=8.4 Hz), 4.85 (s, 2H), 3.13 (s, 3H), 3.05 (s, 3H), 2.41 (s, 3H), 2.26 (s, 3H), 2.09-2.01 (m, 4H), 1.26 (s, 9H), 0.68 (t, 6H, J=7.3 Hz).
HRMS: calcd. for C26H39N2O4S2 (M+1), 507.2351, found, 507.2349.

Example 162

Preparation of 5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide.

[0527] 

[0528] A solution of 5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid dimethylaminemethyleneamide (6.11 g, 12.06 mmol) in 5N HCI/MeOH (180/200 ml) is refluxed overnight. The reaction mixture is concentrated and the residue redissolved in EtOAc (500 ml) and is washed with water (100 ml), brine (100 ml), dried (MgSO₄), concentrated and chromatographed (120 g SiO₂, 60% EtOAc/Hex) to yield the title compound (5.50 g, quant.).
¹NMR (400MHz, CDCl₃) δ 7.01-6.95 (m, 2H), 6.57 (s, 1H), 6.51 (d, 1H, J=7.9 Hz), 4.92 (s, 2H), 4.85 (s, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 2.09-2.03 (m, 4H), 1.25 (s, 9H), 0.69 (t, 6H, =7.3 Hz).
EI-MS: 507.3 (M+1)

Example 163

Preparation of 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid propionyl-amide.

[0529] 

[0530] A mixture of 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methy]-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide (330 mg, 0.73 mmol), EDCI (210 mg, 1.1 mmol), propionic acid (82 µL, 1.1 mmol) and DMAP (50 mg) in dichloromethane (10 ml) is stirrred overnight. The reaction is diluted with dichloromethane and washed with
1N HCl. The organic phase is concentrated and chromatographed (Hex to 30% EtOAc/Hex) to give the title compound (92%).
¹H NMR (CDCl₃) δ 8.10 (s, 1H), 6.98 (s, 1H), 6.97 (d, 1H, J = 8.3 Hz), 6.56 (s, 1H), 6.51 (d, 1H, J = 8.3 Hz), 4.86 (s, 2H), 2.48 (s, 3H), 2.34 (q, 2H), 2.26 (s, 3H), 2.06 (m, 4H), 1.26 (s, 9H), 1.10 (t, 3H), 0.69 (t, 6H);
HRMS: calcd. for C26H41N2O5S2 (M+18), 525.2457, found, 525.2433.

Example 164

Preparation of 5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid isobutyryl-amide.

[0531] 

[0532] Using a procedure analogous to Example 163, 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl} -3-methyl-thiophene-2-sulfonic acid amide and 2-methylpropionic acid give the title compound (56%).
¹NMR (400MHz, CDCl₃) δ 8.00 (s, 1H), 6.99-6.94 (m, 2H), 6.55 (s, 1H), 6.50 (d, 1H, J=8.4 Hz), 4.85 (s, 2H), 2.49 (s, 3H), 2.44 (sept, 1H, J=7.0 Hz), 2.25 (s, 3H), 2.11-2.02 (m, 4H), 1.25 (s, 9H), 1.11 (d, 6H, J=7.0 Hz), 0.68 (t, 6H, J=7.3 Hz).
ES-MS: 522 (M+1)

Example 165

Preparation of 5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid cyclopropanecarbonyl-amide.

[0533] 

[0534] Using a procedure analogous to Example 163, 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide and cyclopropanecarboxylic acid give the title compound (60%).
¹NMR (400MHz, CDCl₃) δ 8.43 (s, 1H), 6.99-6.94 (m, 2H), 6.56 (s, 1H), 6.51 (d, 1H, J=8.4 Hz), 4.86 (s, 2H), 2.46 (s, 3H), 2.25 (s, 3H), 2.12-2.01 (m, 4H), 1.68-1.58 (m, 1H), 1.26 (s, 9H), 1.05-0.99 (m, 2H), 0.89-0.82 (m, 2H), 0.68 (t, 6H, J=7.3 Hz).
EI-MS: 520.2 (M+H), 518.4 (M-H)

Example 166

Preparation of 5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid (2-methoxy-acetyl)-amide.

[0535] 

[0536] Using a procedure analogous to Example 163, 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonic acid amide and methoxy-acetic acid give the title compound (84%).
¹H NMR (CDCl₃) δ 8.9 (s, 1H), 7.00 (s, 1H), 6.97 (dd, 1H, J = 2.6, 8.3 Hz), 6.54 (s, 1H), 6.51 (d, 1H, J = 8.3 Hz), 4.86 (s, 2H), 3.90 (s, 2H), 3.43 (s, 3H), 2.48 (s, 3H), 2.26 (s, 3H), 2.06 (m, 4H), 1.26 (s, 9H), 0.69 (t, 6H);
HRMS: calcd. for C26H41N2O6S2 (M+18), 541.2406, found, 541.2400.

Exampe 169

Preparation of 5-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophen-2-yl)-3H-[1,3,4]oxadiazol-2-one.

[0537] 

[0538] A mixture of 5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid hydrazide (432 mg, lmmol), 1,1'-carbonyldiimidazole (405 mg, 2.5 mmol) and triethylame (0.28 ml, 2 mmol) in THF (10 ml) is stirred at reflux overnight. It is diluted with EtOAc, washed with 1N HCl solution. The organic phase is concentrated and chromatographed (Hex to 20% EtOAc/Hex to give the title compound (290 mag, 63%).
¹H NMR (CDCl₃) δ 8.51.(s,1 1H), 7.05 (dd, 1H, J = 2.4, 8.8 Hz); 7.01 (s, 1H), 6.73 (d, 1H, J = 8.8 Hz), 6.62 (s, 1H), 4.09 (dd, 1H, J = 2.6, 9.2 Hz), 3.87 (dd, 1H, J = 8.8, 9.2 Hz), 3.70 (dd, J = 2.6, 8.8 Hz), 2.42 (s, 3H), 2.20 (s, 3H), 2.08 (m, 4H), 1.01 (s, 9H), 0.69 (t, 6H);
HRMS: calcd. for C25H35N2O4S (M+1), 459.2318, found, 459.2325.

Example 170

Preparation of enantiomer 1 of 5-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophen-2-yl)-3H-[1,3,4]oxadiazol-2-one.

[0539] 

[0540] Using an analogous procedure as Example 169, enantiomer 1 of 5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid hydrazide (Example 168) gives the title compound (65%).
Enantiomer 1: ¹H NMR (CDCl₃) equivalent to Example 169;
HRMS: calcd. for C25H35N2O4S (M+1), 459.2318, found, 459.2321.

Example 171

Preparation of enantiomer of 5-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophen-2-yl)-3H-[1,3,4]oxadiazol-2-one

[0541] 

[0542] Using analogous procedures as in Example 168 and Example 1.69, enantiomer 2 of 1-{4-[1-ethyl-1-(5-methoxycarbonyl-4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-ol (Example 6B) gives the title compound (83%).
Enantiomer 2: ¹H NMR (CDCl₃) equivalent to Example 169;
HRMS: calcd. for C25H35N2O4S (M+1), 459.2318, found, 459.2320.

Example 172

Preparation of 5-(5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophen-2-yl)-3H-[1,3,4]oxadiazole-2-thione.

[0543] 

[0544] A mixture of 5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid hydrazide (432 mg, 1 mmol), carbon disulfide (0.15 ml, 2.5 mmol) and KOH (62 mg, 1.1 mmol) in methanol (15 ml) is refluxed overnight. The reaction is concentrated and partitioned between EtOAc and 1N HCl. The organic phase is concentrated and chromatographed to give the title compound (320 mg, 68%).
¹H NMR (CDCl₃) δ 7.05 (d, 1H, J = 8.3 Hz), 7.00 (s, 1H), 6.74 (d, 1H, J = 8.3 Hz), 6.66 (s, 1H), 4.10 (dd, 1H, J = 2.6, 9.2 Hz), 3.87 (dd, 1H, J = 8.8, 9.2 Hz), 3.71 (dd, J = 2.6, 8.8 Hz), 2.46 (s, 3H), 2.20 (s, 3H), 2.08 (m, 4H), 1.01 (s, 9H), 0.71 (t, 6H);
HRMS: calcd. for C25H35N2O3S2 (M+1), 475.2089, found, 475.2094.

Example 173

Preparation of enantiomer 1 of 5-(5-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophen-2-yl)-3H-[1,3,4]oxadiazole-2-thione.

[0545] 

[0546] Using an analogous procedure as in Example 1,72, enantiomer 1 of 5-{1-ethyl-]-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid hydrazide (Example 168) gives the title compound (72%).
¹H NMR (CDCl₃): equivalent to Example 172;
HRMS: calcd. for C25H35N2O3S2 (M+1), 475.2089, found, 475.2084.

Example 174

Preparation of 5-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester.

[0547] 

A. Trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-methyl-thiophen-2-yl)propyl]-2-methyl-phenyl ester.

[0548] 

[0549] To a mixture of 3'-[4-(hydroxy)-3-methylphenyl]-3'-[4-methylthiophen-2-yl]pentane (8.8 g, 32.2 mmol) and triethylamine (6.8 ml, 48.3 mmol) in dichloromethane (200 nil) at-78 °C is added trifluoromethanesulfonic anhydride (6.5 ml, 38.6 mmol) dropwise and warmed to RT. The reaction is stirred for 1h, diluted with dichloromethane and washed with 0.2 N HCl followed by brine. The organic layer is concentrated to give the title compound (12 g, 92%).

B. 4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-benzoic acid methyl ester.

[0550] 

[0551] A mixture of trifluoromethanesulfonic acid 4-[1-ethyl-1-(4-methyl-thiophen-2-yl) propyl]-2-methyl-phenyl ester (12 g, 29.62 mmol), Pd(OAc)₂ (699 mg, 3 mmol), dppf (3.3 g, 6 mmol), triethylamine (12.5 ml, 90 mmol), methanol (12 ml, 300 mol), and N,N-dimethylformamide (40 ml) is treated with carbon monoxide (1000 psi) at 110 °C in a Parr-reactor for 48 h. The reaction is concentrated, dissolved in is evaporated in EtOAc and filtered through a silica gel pad. The filtrate is concentrated and chromatographed (Hex to 10% EtOAc/Hex) to give the title compound (6.9 g, 73%).
¹H NMR (CDCl₃) δ 7.83 (d, 1H, J = 8.8 Hz), 7.16 (m, 2H), 6.73 (s, 1H), 6.60 (s, 1H), 3.87 (s, 3H), 2.58 (s, 3H), 2.21 (s, 3H), 2.13 (m, 4H), 0.71 (t, 6H).

C. {4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl]-methanol.

[0552] 

[0553] To a 0 °C solution of 4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methylbenzoic acid methyl ester (6.7 g, 21.2 mmol) in THF (100 ml) is added 1M LiAlH₄/THF (32 ml, 32 mmol). After stirring at RT for 2 h, the reaction is quenched with water (1 ml) followed by 5N NaOH solution (1 ml) and water (3 ml). The mixture is filtered and the filtrate is concentrated to give the title compound as a clear oil (6 g, 98%).

D. 1-{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-4,4-dimethyl-pentan-3-one.

[0554] 

[0555] To a 0 °C solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methanol (6 g,) in THF (50 ml) is treated with PBr₃ (2.2 ml, 23.3 mmol) and warmed to RT. After stirring for 2 h, the mixture is partitioned between EtOAc and brine. The organic layer is MgSO₄ dried, concentrated, and dissolved in anhydrous THF (30 ml) to give a solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methane bromide. Separately, a solution of 3,3-dimethyl-butan-2-one (5.3 ml, 42.4 mmol) in THF (15 ml) is treated with LiHMDS (42.4 ml, 42.4 mmol, 1M in THF) at- 70 °C for 1h. This solution is transferred (via cannula) into a-70 °C solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methane bromide/THF. The mixture is warmed to RT and stirred for 1 h. The reaction is diluted with EtOAc and washed with 0.2 N HCl until the aq layer is pH 2. The organic layer is concentrated to give the title compound (6.2 g, 79%).

E. 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-4,4-dimethyl-pentan-3-ol.

[0556] 

[0557] Using a procedure analogous to Example 134B, 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-4,4-dimethyl-pentan-3-one and NaBH₄ give the title compound (quant).
¹H NMR (CDCl₃) δ 7.02, 7.07 (m, 3H), 6.71 (s, 1H), 6.61 (s, 1H), 3.26 (dd, 1H, J = 2.0, 10.3 Hz), 2.88 (m, 1H), 2.56 (m, 1H), 2.28 (s, 3H), 2.20 (s, 3H), 2.08 (m, 4H), 1.78 (m, 1H), 1.58 (m, 1H), 0.90 (s, 9H). 0.70 (t, 6H).

F. tert-Butyl-[1-(2-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2 methyl-phenyl}-ethyl)-2,2-dimethyl-propoxy]-dimethyl-silane.

[0558] 

[0559] Using a procedure analogous to Example 134C, 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-4,4-dimethyl-pentan-3-ol gives the title compound (quant).

G. 5-(1-{4-[3-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-carboxylic acid methyl ester.

[0560] 

[0561] To a 0 °C solution of tert-butyl-[1-(2-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2 methyl-phenyl}-ethyl)-2,2-dimethyl-propoxy]-dimethyl-silane (1.46 g, 3 mmol) in THF (15 ml) is added 1.6 M n-BuLi/Hex (2 ml, 3.3 mmol). After 45 m, the mixture is transferred (via cannula) into a -70 °C solution of methyl chloroformate (0.26 ml, 3.3 mmol) in pentane (10 ml). The mixture is warmed to RT and stirred for 3 h. The reaction is diluted with EtOAc, washed with 0.2 N HCl until the aq layer is pH 2, and followed by washing with satd sodium bicarbonate. The organic layer is concentrated and chromatographed (Hex to 5% EtOAc/Hex) to give the title compound (1.05 g, 64%).
¹H NMR (CDCl₃) δ 6.99, 7.04 (m, 3H), 6.62 (s, 1H), 3.80 (s, 3H), 3.35 (dd, 1H, J = 2.9, 7.3 Hz), 2.76 (m, 1H), 2.48 (s, 3H), 2.41 (m, 1H), 2.26 (s, 3H), 2.08 (m, 4H), 1.78 (m, 1H), 1.59 (m, 1H), 0.93 (s, 9H), 0.88 (s, 9H), 0.70 (t, 6H), 0.10 (s, 3H), 0.07 (s, 3H).

H. 5-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester.

[0562] 

[0563] Using a procedure analogous to Example 134F, 5-(1-{4-[3-(tert-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-carboxylic acid methyl ester gives the title compound (94%).
¹H NMR (CDCl₃) δ 7.00, 7.07 (m, 3H), 6.62 (s, 1H), 3.80 (s, 3H), 3.25 (dd, 1H, J = 1.8, 10.5 Hz), 2.88 (m, 1H), 2.55 (m, 1H), 2.48 (s, 3H), 2.28 (s, 3H), 2.08 (m, 4H), 1.79 (m, 1H), 1.58 (m, 1H), 0.90 (s, 9H), 0.70 (t, 6H);
HRMS: calcd. for C26H38O3NaS (M+23), 453.2439, found 453.2465.

Example 175

Preparation of 5-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid.

[0564] 

[0565] Using LiOH hydrolysis as described in Example 137, 5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester gives the title compound (94%).
¹H NMR (CDCl₃) δ 7.00, 7.07 (m, 3H), 6.62 (s, 1H), 3.25 (dd, 1H, J = 1.8, 10.5 Hz), 2.88 (m, 1H), 2.55 (m, 1H), 2.48 (s, 3H), 2.28 (s, 3H), 2.08 (m, 4H), 1.79 (m, 1H), 1.58 (m, 1H), 0.90 (s, 9H), 0.70 (t, 6H);
HRMS: calcd. for C25H36O3NaS (M+23), 439.2283, found 439.2283.

Example 176

Preparation of [(5-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amine]-acetic acid methyl ester.

[0566] 

[0567] A mixture of 5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl)-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid (160 mg, 0.38 mmol), 2-amino-acetic acid methyl ester hydrochloride (53 mg, 0.42 mmol), EDCI (89 mg, 0.46 mmol) and triethylamine (0.134 ml, 0.96 mmol) in dichloromethane (5 ml) is stirred at RT overnight. The reaction is concentrated, partitioned between 1N HCl and EtOAc. The organic layer is concentrated and chromatographed (Hex to 30% EtOAc/Hex) to give the title compound (75 mg, 40%).
¹H NMR (CDCl₃) δ 7.07 (d, 1H, J = 8.7 Hz), 7.00 (d, 1H, J = 8.7 Hz), 6.99 (s, 1H), 6.63 (s, 1H), 6.20 (t, 1H), 4.16 (d, 2H, J = 5.3 Hz), 3.78 (s, 3H), 3.26 (bd, 1H, J = 9.3 Hz), 2.88 (m, 1H), 2.56 (m, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 2.08 (m, 4H), 1.78 (m, 1H), 1.58 (m, 1H), 0.90 (s, 9H), 0.70 (t, 6H).
ES-MS: 488 (M+1).

Example 177

Preparation of [(5-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid.

[0568] 

[0569] Using LiOH hydrolysis as described in Example 136, [(5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid methyl ester gives the title compound (quant).
¹HNMR (CDCl₃) δ 7.07 (d, 1H, J = 8.7 Hz), 7.00 (d, 1H, = 8.7 Hz), 6.99 (s, 1H), 6.63 (s, 1H), 6.21 (t, 1H), 4.20 (d, 2H, J = 5.3 Hz), 3.26 (bd, 1H, J = 9.3 Hz), 2.88 (m, 1H), 2.56 (m, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 2.08 (m, 4H), 1.78 (m, 1H), 1.58 (m, 1H), 0.90 (s, 9H), 0.70 (t, 6H);
HRMS: calcd. for C27H40NO4S (M+1), 474.2678, found 474.2687.

Example 178

Preparation of (5-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl)-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester.

[0570] 

[0571] Using procedures analogous to Example 134D to Example 134F, from tert-butyl-[1-(2-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2 methyl-phenyl}-ethyl)-2,2-dimethyl-propoxy]-dimethyl-silane and 2-amino-acetic acid methyl ester hydrochloride gives the title compound (24%).
¹H NMR (CDCl₃) δ 7.07 (d, 1H, J = 7.9 Hz), 7.02 (s, 1H), 6.97 (d, 1H, J = 7.9 Hz), 6.64 (s, 1H), 5.12 (t, 1H), 3.82 (d, 2H, J = 5.3 Hz), 3.65 (s, 3H), 3.32 (d, 1H, J = 9.3 Hz), 2.88 (m, 1H), 2.56 (m, 1H), 2.42 (s, 3H), 2.30 (s, 3H), 2.08 (m, 4H), 1.88 (m. 1H), 1.54 (m, 1 H), 0.87 (s, 9H), 0.72 (t, 6H).
ES-MS: 524 (M+1).

Example 179

(5-{1-Ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sultonylamino)-acetic acid.

[0572] 

[0573] Using LiOH hydrolysis as described in Example 136, (5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester gives the title compound (quant).
¹H NMR (CDCl₃) δ 7.08 (d, 1H, J = 7.9 Hz), 7.03 (s, 1H), 6.98 (d; 1H, J = 7.9 Hz), 6.65 (s, 1H), 5.12 (t, 1 H), 3.82 (d, 2H, J = 5.3 Hz), 3.32 (d, 1H, J = 9.3 Hz), 2.88 (m, 1H), 2.56 (m, 1H), 2.42 (s, 3H), 2.30 (s, 3H), 2.08 (m, 4H), 1.88 (m, 1H), 1.54 (m, 1H), 0.87 (s, 9H), 0.72 (t, 6H).
HRMS: calcd. for C26H43N2O5S2 (M+18), 527.2613, found 527.2639.

Example 180 and Example 181

Preparation of enantiomers of (5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylaminoo)-acetic acid.

[0574] 

[0575] A racemic mixture of (5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamide)-acetic acid (180 mg) is chromatographed on a Chiralpak AD column (0.46 x 25 cm) to give the title compounds.
HPLC condition: 0.1% trfluoroacetic acid in 30% isopropanol/hept; flow rate: 1.0 ml/m;
UV: 225 nm.
Enantiomer 1, Example 179: 70 mg (39%); rt: 6.63 m;
¹H NMR (CDCl₃) equivalent to Example 179
HRMS: calcd. for C26H40NO5S2 (M+1), 510.2348, found 510.2333.
Enantiomer 2, Example 180: 60 mg (33%); rt: 8.60 m.
¹H NMR (CDCl₃) equivalent to Example 179;
HRMS: calcd. for C26H40NO5S2 (M+1), 510.2348, found 510.2359.

Example 183

Preparation of (5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-ylmethylsulfanyl)-acetic acid ethyl ester.

[0576] 

A. (5-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-yl)-methanol.

[0577] 

[0578] To a 0 °C solution of 5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester (10.0 g, 22.39 mmol) in THF (200 ml) is added portionwise lithium aluminum hydride (1.70 g, 44.78 mmol) and the reaction mixture is warmed to RT for 1 h. The reaction is quenched with water (1.7 ml), 5N NaOH (1.7 ml), and water (5.1 ml). The reaction mixture is filtered, concentrated and chromatographed (120 g SiO₂, 10% EtOAc/Hex) to yield the title compound (7.0 g, 75%).
¹NMR (400MHz, CDCl₃) δ 7.01 (d, 1H, J=2.2 Hz), 6.94 (dd, 1H, J=8.4, 2.2 Hz), 6.65 (d, 1H, J=8.4 Hz), 6.52 (s, 1H), 4.65 (d, 2H, J=4.8 Hz), 2.17 (s, 6H), 2.09-1.99 (m, 4H), 1.54 (t, 1H, J=5.5 Hz), 1.00 (s, 9H), 0.69 (t, 6H, J=7.3 Hz), 0.20 (s, 6H).

B. Toluene-4-sulfonic acid 5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-ylmethyl ester.

[0579] 

[0580] To a solution of (5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-yl)-methanol (1.0 g, 2.39 mmol) in Et₂O (5 ml) is added triethyl amine (666 µl, 4.78 mmol). The mixture is added to a solution of p-toluenesulfonyl chloride (501 mg, 2.62 mmol) in Et₂O (5 ml) and stirred overnight. The reaction is filtered, concentrated and chromatographed (12 g SiO₂, 5% EtOAc/Hex) to yield the title compound (740 mg, 55%).
¹NMR (400MHz, CDCl₃) δ 7.93 (d, 2H, J=8.4 Hz), 7.41 (d, 2H, J=8.8 Hz), 7.00 (s, 1H), 6.93 (dd, 1H, J=8.4, 2.2 Hz), 6.63 (d, 1H, J=8.4 Hz), 6.48 (s, 1H), 4.49 (s, 2H), 2.49 (s, 3H), 2.15 (s, 3H), 2.09 (s, 3H), 2.05-2.00 (m, 4H), 0.99 (s, 9H), 0.67 (t, 6H, J=7.3 Hz), 0.19 (s, 6H).
EI-MS: 401.2

C. (5-{1-[4-(tert-Butyl-dimethyl-slianyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-ylmethylsulfanyl)-acetic acid ethyl ester.

[0581] 

[0582] To a solution of 2.68 M sodium ethoxide (507 µl, 1.36 mmol) in EtOH (2 ml) is added ethyl 2-mercaptoacetate (149 µl, 1.36 mmol) and stirred at RT for 30 m. The mixture is added a solution of toluene-4-sulfonic acid 5-{1-[4-(tert-butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-ylmethyl ester (740 mg, 1.29 mmol) in EtOH (2 ml) is added and refluxed for 15 m. The reaction is concentrated and partitioned between EtOAc (100 ml) and 0.2N HCl (50 ml). The organic layer is washed with water (50 ml), dried (MgSO₄), concentrated, and chromatographed (12 g SiO₂, 5% EtOAc/Hex) to yield the title compound (180 mg, 27%).
¹NMR (400MHz, CDCl₃) δ 7.00 (d, 1H, J=2.2 Hz), 6.92 (dd, 1H, J=8.4, 2.2 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.46 (s, 1H), 4.17 (q, 2H, J=7.2 Hz), 3.92 (s, 2H), 3.14 (s, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 2.07-1.98 (m, 4H), 1.28 (t, 3H, J=7.0 Hz), 1.00 (s, 9H), 0.68 (t, 6H, J=7.3 Hz), 0.20 (s, 6H).
EI-MS: 538.2 (M+NH₄)

D. {5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophen-2-ylmethylsulfanyl}-acetic acid ethyl ester.

[0583] 

[0584] Using an analogous procedure to Example 12F, (5-{1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-ylmethylsulfanyl)-acetic acid ethyl ester (180 mg, 0.346 mmol) gives the title compound (147 mg, quant.). ¹NMR (400MHz, CDCl₃) δ 7.00 (s, 1H), 6.97 (d, 1H, J=7.9 Hz), 6.67 (d, 1H, J=8.4 Hz), 6.47 (s, 1H), 4.58 (s, 1H), 4.17 (q, 2H, J=7.2 Hz), 3.92 (s, 2H), 3.14 (s, 2H), 2.21 (s, 3H), 2.12 (s, 3H), 2.06-1.99 (m, 4H), 1.28 (t, 3H, J=7.0 Hz), 0.68 (t, 6H, J=7.3 Hz).

E. (5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophen-2-ylmethylsulfanyl)-acetic acid ethyl ester.

[0585] 

[0586] Using an analogous procedure to Example 134A, {5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophen-2-ylmethylsulfanyl}-acetic acid ethyl ester (141 mg, 0.347 mmol) gives the title compound (145 mg, 83%).
¹NMR (400MHz, CDCl₃) δ 7.02 (s, 1H), 7.00 (d, 1H, J=8.4 Hz), 6.51 (d, 1H, J=8.4 Hz), 6.46 (s, 1H), 4.83 (s, 2H), 4.17 (q, 2H, J=7.2 Hz), 3.92 (s, 2H), 3.14 (s, 2H), 2.25 (s, 3H), 2.12 (s, 3H), 2.08-1.97 (m, 4H), 1.30-1.19 (m, 12H), 0.67 (t, 6H, J=7.3 Hz).
EI-MS: 522.2 (M+NH₄).

Example 184

Preparation of 3'-[4-(2-Oxo-3,3-dimethylbutoxy-3-methylphenyl)]-3'-[5-(methylmercaptylmethyl)thiophen-2-yl]pentane.

[0587] 

L. 2-(Methylmercaptylmethyl)-thiophene.

[0588] 

[0589] To a 25 °C solution of 2-hydroxymethyl thiophene (2.28 g, 20 mmol), and S-methyl-N,N'tetramethylisothiouronium iodide [(5.48 g, 20 mmol); [S. Fujisaki et al, Bull. Chem. Soc. Jpn., 58, 2429-30 (1985)] in anhydrous DMF (10 ml) under a N₂ atmosphere, is added NaH (1.44 g, 60 mmol, 2.40 g of 60% mineral oil dispersion) in small portions. After the resulting vigorous liberation of hydrogen ceases, hexane (10 ml) is added. After stirring for 1 h, the reaction is cooled to 0 °C and water (10 ml) is added dropwise. The mixture is extracted with hexane (3 X 50 ml). The combined extract is K₂CO₃, concentrated, and chromatographed with (Hex to 20% CHCl₃/Hex) to give the title compound as a colorless liquid (2.4 g, 83%).
¹NMR (300MHz, CDCl₃) δ ppm: 2.10 (s, 3H), 3.92 (s, 2H), 6.95 (m, 2H), 7.23 (1H).

M. 3'-[4-(Hydroxy)-3-methylphenyl]-3'-[5-(methylmercaptylmethyl)thiophen-2-yl]pentane.

[0590] 

[0591] To a 0 °C mixture of 3'-[4-(hydroxy)-3-methylphenyl]pentan-3-ol (582 mg, 3.0 mmol) and 2-(methylmercaptylmethyl)-thiophene (2.16 g, 15.0 mmol) is added BF₃-Et₂O (171 mg, 0.15 ml, 1.20 mmol). After stirring for 30 m at 0 to 5 °C, the reaction is quenched with satd aq NaHCO₃ and is extracted with EtOAc (2X). The combined extract is washed with brine, Na₂SO₄ dried, concentrated, and chromatographed by radial chromatography (4 mm plate, 25% to 80% CHCl₃/Hex to give the title compound as a pale brown oil (695 mg, 72%).
¹NMR (300MHz, CDCl₃) δ ppm: 0.0.71 (t, J = 7.3 Hz, 6H), 2.06 (s, 3H), 2.07 (m, 4H), 2.23 (s, 3H), 3.82 (s, 3H), 4.52 (s, 1H), 6.60 to 6.75 (m, 3H), 6.96-7.05 (m, 2H). TOF(+) MS m/z: 320.2; calc. for C₁₈H₂₄OS₂: 320.20.
ES (-) MS m/z 319.1, [M-H]; calc. for C₁₈H₂₃OS₂: 319.24.

C. 3'-[4-(2-Oxo-3,3-dimethylbutoxy-3-methylphenyl)]-3'-[5-(methylmercaptylmethyl)-thiophen-2-yl]pentane.

[0592] 

[0593] To a mixture of 3'-[4-(hydroxy)-3-methylphenyl]-3'-[5-(methylmercaptylmethyl)-thiophen-2-yl]pentane (586 mg, 1.83 mmol), KI (122 mg, 0.73 mmol), 3,3-dimethyl-1-chloro-2-butanone (370 mg, 2.75 mmol) and DMF (10 ml) at 25 °C is added 60% NaH dispersion (92 mg, 2.29 mmol) in small portions. The reaction is stirred for 15 m and quenched with satd NaHCO₃ solution (50 ml). The mixture is extracted with EtOAc (2 X 50 ml) and the combined organic layer is washed with brine, Na2SO4 dried, and concentrated. The resulting oil is radial chromatographed (50% to 75% CHCl3/Hex) to give the title product as a pale yellow oil (516 mg, 67%).
¹NMR (400MHz, DMSO-d₆) δ ppm: 0.64 (t, J = 7.3 Hz, 6H), 1.18 (s, 9H), 1.97 (s, 3H), 2.02 (m, 4H), 2.15 (s, 3H), 3.84 (s, 2H), 5.07 (s, 2H), 6.55 to 6.76 (m, 3H), 6.93 to 7.04 (m, 2H).
FAB(+) MS m/z [M-H]: 417.3; calc. for C₂₄H₃₄O₂S₂(-H): 417.20
IR (CHCl₃) : 1724.08 cm^-1.

Example 185

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy) -3-methylphenyl]-3'-[5-(methylmercaptylmethyl)-thiophen-2-yl]pentane.

[0594] 

[0595] To a 25 °C solution of 3'-[4-(2-Oxo-3,3-dimethylbutoxy-3-methylphenyl)]-3'-[5-(methylmercaptylmethyl)thiophen-2-yl]pentane (90 mg, 0.22 mmol) in MeOH (10 ml) is added NaBH₄ (8.1 mg, 0.22 mmol). The reaction mixture is stirred overnight at ambient temperature. Then 1 ml of acetone is added, the reaction is concentrated and the residue is distributed between H₂O and CH₂Cl₂. The organic layer is washed with water, dried with anhydrous Na₂SO₄, and concentrated to give the title compound as a colorless oil (90 mg, quant).
¹NMR (300MHz, CDCl₃) δ ppm: 0.63 (t, J = 7.3 Hz, 6H), 0.94 (s, 9H), 1.95-2.08 (m, 4H), 1.97 (s, 3H), 2.12 (s, 3H), 3.63 (m, 1H), 3.73 (s, 2H), 3.79 (dd, J = 7.3, 10.2 Hz, 1H), 4.02 (dd, J = 3.4, 10.2 Hz, 1H), 6.54 (m, 1H), 6.64 (m, 2H), 6.97 (m, 2H).
FAB(+) MS m/z [M-H]: 419.3; calc. for C₂₄H₃₆O₂S₂ (-H): 419.22.
ES (+) MS m/z 438.2, [MNH₄+]; calc. for C₂₄H₄₀NO₂S_2: 438.24.

Example 186A and Example 186B

Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy-3-methylphenyl)]-3'-[5-(methylmercaptylmethyl)-thiophen-2-yl]pentane.

[0596] 

[0597] A racemic mixture of 3'-[4-(2-oxo-3,3-dimethylbutoxy-3-methylphenyl)]-3'-[5-(methylmercaptylmethyl)thiophen-2-yl]pentane (76 mg) is chromatographed with a Chiralcel AD column to give enantiomer 1, Example 186A (28 mg, 37%) and enantiomer 2, Example 186B (22 mg, 29%).
Enantiomer 1, Example 186A
HPLC: Chiralcel AD (4.6X250 mm); 40% IPA/60% heptane; 1 ml/m (flow rate); rt = 4.21 m; 225 nm; ee 100% by HPLC.
FAB(+) MS m/z [M-H]: 419.3; calc. for C₂₄H₃₆O₂S₂ (-H): 419.22.
Enantiomer 2, Example 186B
HPLC: Chiralcel AD (4.6X250 mm); 40% IPA/60% heptane; 1 ml/m (flow rate); rt = 5.67 m; 225 nm; ee 100% by HPLC.
FAB(+) MS m/z [M-H]: 419.3; calc. for C₂₄H₃₆O₂S₂ (-H): 419.22.

Example 187

Preparation of 3'-[4-(2-oxo-3,3-dimethylbutoxy-3-methylphenyl)]-3'-[5-(methylsulphonylmethyl)-thiophen-2-yl]pentane.

[0598] 

[0599] Using a procedure analogous to Example 9C, 3'-[4-(2-oxo-3,3-dimethylbutoxy-3-methylphenyl)]-3'-[5-(methylmercaptylmethyl)-thiophen-2-yl]pentane gives the title compound as a pale yellow oil (287 mg, 85%).
¹NMR (300MHz, CDCl₃) δ ppm: 0.71 (t, J = 7.3 Hz, 6H), 1.28 (s, 9H), 2.04-2.25 (m, 4H), 2.27 (s, 3H), 2.79 (s, 3H), 4.37 (s, 2H), 4.86 (s, 2H), 6.53 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 3.6 Hz, 1H), 6.99 to 7.02 (m, 3H).
FAB(+) MS m/z: 452.3; calc. for C₂₄H₃₄O₄S₂: 450.19.
ES (+) MS m/z 468.2, [MNH₄+]; calc. for C₂₄H₃₈NO₄S₂: 468.22.
IR (CHCl₃): 1725.04 cm^-1.
UV (EtOH): 227 nm (e = 17500), 255 nm (shoulder, e = 10,000).

Example 188

Preparation of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-(methylsulfonylmethyl)-thiophen-2-yl]pentane.

[0600] 

[0601] Using a procedure analogous to Example 2, 3'-[4-(2-oxo-3,3-dimethylbutoxy-3-methylphenyl)]-3'-[5-(methylsulfonylmethyl)-thiophen-2-yl]pentane gives the title compound as a colorless oil (188 mg, 94%).
¹NMR (400MHz, EDCl₃) δ ppm: 0.67 (t, J = 7.3 Hz, 6H), 1.04 (s, 9H), 2.12 (m, 4H), 2.22 (s, 3H), 2.14 (s, 3H), 2.80 (s, 3H), 3.72 (m, 1H), 3.99 (m, 1H), 4.12 (dd, J = 2.9, 9.8 Hz, 1H), 4.36 (s, 2H), 6.74 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 3.6 Hz, 1H), 6.96 to 7.08 (m, 3H).
FAB(+) MS m/z: 452.3; calc. for C₂₄H₃₆O₄S₂: 452.21.

Example 189A and Example 189B:

[0602] Preparation of enantiomers of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-(methylsulfonylmethyl)-thiophen-2-yl]pentane.

[0603] A racemic mixture of 3'-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]-3'-[5-(methylsulfonylmethyl)-thiophen-2-yl]pentane (174 mg) is chromatographed (Chiralcel AD column) to give enantiomer 1, Example 189A (78 mg, 43%) and enantiomer 2, Example 189B (86 mg, 49%).
Enantiomer 1, Example 189A
HPLC: Chiralcel AD (4.6X250 mm); 40% IPA/60% heptane; 1 ml/m (flow rate); rt = 5.75 m; 240 nm; ee = 99.8%.
FAB(+) MS m/z: 452.3; calc. for C₂₄H₃₆O₄S₂: 452.21.
ES (+) MS m/z 470.1, [MNH₄+]; calc. for C₂₄H₄₀NO₄S₂: 470.24.
Enantiomer 2, Example 189B
HPLC: Chiralcel AD (4.6X250 mm); 40% IPA/60% heptane; 1 ml/m (flow rate); rt = 7.75 m; 260 nm; ee = 99.6%.
FAB(+) MS m/z: 452.3; calc. for C₂₄H₃₆O₄S₂: 452.21.
ES (+) MS m/z 470.1, [MNH₄+]; calc. for C₂₄H₄₀NO₄S₂: 470.24.

Methods of Using the Compounds of the Invention:

[0604] When administration of the Active Ingredient is to be parenteral, such as intravenous on a daily basis, injectable pharmaceuticals may be prepared in conventional forms, either as liquid Solutions or suspensions; solid forms suitable for solution or suspension in liquid prior to injection; or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, or the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. If desired, absorption enhancing preparations (e.g. liposomes) may be utilized.

Experimental Results:

[0605] 

Table 5

Test Cmpd.1	RXR-VDR (SaOS-2 cells)2 EC50 (nM)	VDR CTF (Caco-2 cells)3 EC50 (nM)	OCN Promoter4 EC50 (nM)	Mouse Hypercal5 µg/Kg/d
Ex. 1		3696	140.5
Ex. 2		1112	30.65	>1000
Ex. 3			72.675	3000
Ex. 4		374	147.2	1000
Ex. 5		1027	146.1	>3000
Ex. 6A	81.54	599.84	63.8	1000
Ex. 6B	323.06	1056.5	325.57	>6000
Ex. 7	397.36	274.50	112.35	6000
Ex. 8	956.98		367.2	>3000
Ex. 9	295.3	1091.1	46.65	6000
Ex. 10	58.89	80.71	51.31
Ex. 11A	18.12	206.61	42.75	1500
Ex. 11B	96.14	365.96	150.15
Ex. 13	-	-	312.7	-
Ex. 14	85.30	264.11	46.65
Ex. 15A	40.57	361.28	46.82	>1000
Ex. 15B	211.66	244.69	19.72	9000
Ex. 18	9.00	551.78	11.16
Ex. 19A	14.24	310.59	26.2	>3000
Ex. 19B	186.18	450.04	10.2	>1000
Ex. 20			862
Ex. 21			139.7
Ex. 24	560.73		4.7
Ex. 25A	96.27	699.28	9.9
Ex. 26	74.54	589.16	7.95	1000
Ex. 27			49.1	>3000
Ex. 28		535.75	0.76
Ex. 29	269.60	790.90	8.65
Ex. 30A	24.88	573.73	11.22	1000
Ex. 30B	150.40	1046.08	14.1	2000
Ex. 31	513.63	1919.23	7.8
Ex. 32	2025.58		9.35
Ex. 33A	136.16	1697.32	43.55	>9000
Ex. 33B	94.61	778.39	7.55	1000
Ex. 34	735.72	1228.95	96.8	3000
Ex. 35	311.89	1166.83	21.13	3000
Ex. 36	185.38	702.55	67.87	2000
Ex. 37	441.60		239.87
Ex. 38			379.5
Ex. 39	189.14		299.66
Ex. 40	450.82		612.8
Ex. 41			300.5
Ex. 42	10.74	1154.56	33.5
Ex. 43	80.55	598.43	19.7	1000
Ex. 44	584.10	910.97	30.4	1000
Ex. 45	23.76	1671.30	40.95	>1500
Ex. 46	2.495	855.72	43.6
Ex. 47	10.047		27.7
Ex. 48	176.42	949.33	12.3	3000
Ex. 49	526.80	798.80	62.34	>3000
Ex. 50	186.85	1480.00	21.63	>3000
Ex. 51			781
Ex. 53	821.55		267.2
Ex. 54	465.43	1436.67	27.5
Ex. 55	170.75	779.46	29.63	1000
Ex. 56			164.1
Ex. 57			114.95
Ex. 58			276.7
Ex. 64	173.87	411.13	4.1
Ex. 65	23.39	497.97	3.4	300
Ex. 66	313.33	1457.87	28.45
Ex. 69	558.83		487.1
Ex. 70	149.36	1377.99	25.8
Ex. 71	137.79	497.41	3.5	<300
Ex. 72	498.39	1026.70	218.55
Ex. 74	319.27		478.
Ex. 75	722.03		423.17
Ex. 76	552.77		57.8
Ex. 77	53.70	534.56	2	300
Ex. 81	381.62		200
Ex. 82	1284
Ex. 86	321.74		204.6
Ex. 87	744		>1000
Ex. 88	469.50		168.83
Ex. 89	286.16	360.27	313.67
Ex. 90	656	1312
Ex. 91			212
Ex. 92			75.35	1000
Ex. 93		598.50	38.5	3000
Ex. 94	51.08	599.40	4.05	1000
Ex. 95	420.73	1176.73	21.45	>6000
Ex. 97	16.67	858.15	22.45	3000
Ex. 98	65.30	1019.59	15.85	4000
Ex. 99			38.1	>1000
Ex. 100	53.13	615.07	5.63	3000
Ex. 101	379.25		29.35	12000
Ex. 103	548.21	1284.03	102.35	3000
Ex. 104	286.18	801.07	90.93	1000
Ex. 105	633.62		735.55
Ex. 106	83.75	899.38	8.05	>=1000
Ex. 107	372.20	1031.12	42.3
Ex. 108	159.89	352.20	5.25	300
Ex. 110	18.81	113.37	0.225	<300
Ex. 111	188.97	319.84	34.45
Ex. 112	485	658	5
Ex. 113	542		118
Ex. 114	8.13	85.02	0.28	<300
Ex. 118	384.82		32.25
Ex. 122	526.60		67.45
Ex. 123	667.80		474.65
Ex. 124	453.07		101
Ex. 125			144.2
Ex. 126	2.754	358.01	111.4
Ex. 127	38.19	1503.75	956
Ex. 128	433.89	2522.75	12.6
Ex. 129	390.64		68.4
Ex. 130	336.51	1105.33	49.7
Ex. 131	461.51	693.30	59.35	3000
Ex. 132	355.90	969.29	51.25	1000
Ex. 134	4.05	1302.99	30.6
Ex. 135	318.10	620.06	29.9
Ex. 136	430.68	901.03	145.8
Ex. 137	409.00		24.2	>3000
Ex. 138	476.09	1060.24	27.13	2000
Ex. 139	479.30		30.97	>3000
Ex. 140	436.81		72.45
Ex. 141	196.86		43.7
Ex. 142 2123818	604.77	783.08	113.7	3000
Ex. 143	735.29		687.93
Ex. 144	687.94	1513.74	29.2	3000
Ex. 145	284.27		221.8
Ex. 146	676.02		27.7	>3000
Ex. 147	351.94		128.27
Ex. 148	848.32	1146.189	236.2
Ex. 149	371.94	1206.25	98.35
Ex. 150	103.99	1128.4	55.2
Ex. 152	473.97		110
Ex. 153	376.02		187
Ex. 154	171.33	470.46	20.5
Ex. 155	270.66	799.30	18.4	6000
Ex. 157	235.83	484.31	7.65	>1000
Ex. 158	732.37	2414.37	84.97
Ex. 159	400.62	1336.75	89.67
Ex. 160	900.63		40.3	3000
Ex. 161			77
Ex. 162			131
Ex. 163	649.14		105.9
Ex. 164	1054.86		150.4
Ex. 165	1783.20		137.7
Ex. 166	1072.82		151
Ex. 169	80.70	370.91	17.65	<1000
Ex. 170	96.53	589.04	8.4	1000
Ex. 171	229.78	930.62	92.6
Ex. 172	417.83	781.88	17.2
Ex. 173	80.93	645.18	25.4	3000
Ex. 174	58.90	1100.63	172
Ex. 175	687.78		126.9
Ex. 176	135.98	288.78	174.2
Ex. 177	362.21		45.97
Ex. 178			25.5
Ex. 179	142.50	279.42	27.85
Ex. 180	394.35	603.53	40.52	>3000
Ex. 181	403.35	645.03	83.57	>3000
Ex.183	134.13	781.17	38.6
AA	5.02	16	5	0.06
BB	10.32	169.81	8.24	>=20
CC	2427.7		>1000
DD	109.44		31.1	1000
EE	429.99	891.16	34'1.25	1000
FF	3	57

Table 6

Summary of Experimental Results
Test Cmpd.1	Kera. Prolif. IC50 (nM)	IL-10 IC50 (nM)
Ex. 1
Ex. 2
Ex. 3
Ex. 4	122.5
Ex. 5
Ex. 6A	439.0
Ex. 9	129	98
Ex. 10	25.0
Ex. 11A
Ex. 11B	216.0
Ex. 15A	76	26
Ex. 15B	84.0	66
Ex. 18	24.5
Ex. 19A	18	60
Ex. 19B	20	48
Ex. 29	4.6
Ex. 30A	13.0
Ex. 30B	40	120
Ex. 33B	22.5
Ex. 35	474.0
Ex. 39	367.0
Ex. 48	71.5
Ex. 49	430.0
Ex. 55	0.1
Ex. 65	56	41
Ex. 66	277.0
Ex. 71	29.0
Ex. 77	194.0
Ex. 89	105.0
Ex. 93	178.0
Ex. 100	215.0
Ex. 106	13.0
Ex. 108	66.0	597
Ex. 110	9.5	288
Ex. 124	216.3
Ex. 138	102.0	110
Ex. 142	300.0
Ex. 145	702.0
Ex. 155	788.0
Ex. 158	500.0
Ex. 159	234.3
Ex. 160	1095.0
Ex. 169	522.0
Ex. 170	36	100
Ex. 173	478.0
Ex. 176	114.0
Ex. 177	81.3
Ex. 179	221.0
AA	120	1.2
BB	10	28
CC	-	-
DD	1060
EE
FF	103	0.5

[0606] Explanation of Table 5 and 6 column numerical superscripts:

1. Test Compound numbers refer to the products of the corresponding Example Nos. that is, compounds within the scope of the invention. For example, the number "Ex. 2" refers to the compound, 3'-[4-(2-hydroxy-3,3-dimethylbutoxy) -3-methylphenyl]-3'-[5-methoxycarbonyl-4-methylthiophen-2-yl]pentane, prepared in Example 2. The control experiments are done with the double letter coded compounds identified as follows:

"AA" = 1α,25-dihydroxyvitamin D₃

"BB" = 3-(4-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-phenoxy)-propane-1,2-diol "CC" = 1-(4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-cyclohexyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one

"DD" = compound represented by the formula:

"EE" = compound represented by the formula:

calcipotriol (structural formula below):

2. The RXR-VDR heterodimerization (SaOS-2 cells) test is described in the "Assay" section of the Description, infra.

3. The VDR CTF (Caco-2 cells) test is described in the "Assay" section of the Description, infra.

4. The OCN Promoter test is described in the "Assay" section of the Description, infra.

5. The Mouse Hypercalcemia test is described in the "Assay" section of the Description, infra.

6. The keratinocyte proliferation assay is described in the "Assay" section of the Description, infra.

7. The IL-10 induction assay is described in the "Assay" section of the Description, infra.

Assay Methods

Use of the Assay Methods:

[0607] The evaluation of the novel compounds of the invention for osteoporosis and other related diseases is done using a plurality of test results. The use of multiple assays is necessary since the combined properties of (i) high activity for the vitamin D receptor, and (ii) prevention of hypercalcemia must be achieved to have utility for the methods of treating diseases, which are also, aspects of this invention. Some of the tests described below are believed related to other tests and measure related properties of compounds. Consequently, a compound may be considered to have utility in the practice of the invention if is meets most, if not all, of the acceptance criteria for the above described tests.

[0608] The evaluation of the novel compounds of the invention for psoriasis is done using the Keratinocyte Proliferation Assay in combination with other assays that measure inhibition of IL-2 production and stimulation of IL-10 production in peripheral blood mononuclear cells (PBMCs).

Brief Description, Utility and Acceptance Criteria for the Assay Methods:

1. The RXR-VDR heterodimerAssay:

[0609] This assay provides the VDR activity of a test compound. It is desirable to have low EC50 values for a compound in this assay. The lower the EC50 value, the more active the compound will be as a VDR agonist. Desired assay results are EC50 values less than or equal to 600 nM. Preferred assay results are less than 250 nM, and most preferably less than 150 nM.

2. The Caco-2 cell Co-transfection Assay:

[0610] The Caco-2 cell assay is an indicator for the undesirable condition of hypercalcemia. This co-transfection assay is a surrogate assay for in vivo calcemic activity of VDR ligands. It is desirable to have high EC50 values for a test compound in this assay. The higher the EC50 values for a compound the less calcemic it will be in vivo. Desired assay results are EC50 greater than or equal to 300 nM. Preferred assay results are greater than 1000 nM.

3. The OCN (osteocalcin) Promoter Assay

[0611] The OCN Promoter Assay is an indicator and marker for osteoporosis. Desired assay results are EC50 less than or equal to 325 nM. Preferred assay results are less than 50 nM.

4. The Mouse Hypercalcemia Assay

[0612] The Mouse Hypercalcemia Assay is a six day hypercalcemia test for toxicity and selectivity. Acceptable test results are levels greater than 300 µg/kg/day. Preferred assay results are levels greater than 1000 µg/kg/day.

5. The Keratinocyte Proliferation Assay

[0613] This Assay is indicative for the treatment of psoriasis. An acceptable test result is IC50 value of less than or equal to 300 nM. Preferred assay results are IC50 values of less than 100 nM.

6. The IL-10 induction Assay

[0614] This is an in vitro efficacy assay for psoriasis, abscess and adhesion. Psoriasis involves both keratinocytes and immune cells. IL-10 is a unique cytokine because it is antiinflammatory and immunosuppressive. This assay tells us whether a VDRM is able to function as an agonist in PBMCs (primary blood mononuclear cells) or not. A lower EC50 value is desirable in this assay since a compound with a lower EC50 value will be a better agonist in PBMCs. An acceptable test result is an EC50 value of less than 200 nM. Preferred assay results are EC50 values of less than 100 nM.

Details of the Assay Methods:

(1) Materials and Method for RXR-VDR Heterodimerization Assay:

Transfection Method:

[0615] 

• FuGENE 6 Transfection Reagent (Roche Cat # 1 814 443)

Growth Media:

[0616] 

• D-MEM High Glucose (Gibco BRL Cat # 11054-020), 10% FBS, 1% antibiotic-antimycotic (Ab-Am)

FBS heat inactivated (Gibco BRL Cat # 10092-147)
Ab-Am (Gibco BRL Cat # 15240-062)

Cells:

[0617] 

• Grow SaOs-2 cells in T-152 cm² culture flasks in growth media.
• Keep the density at 5-6 x 10⁵ cells/ml
• Passage cells 1:3 twice a week
• Add Trypsin EDTA (Gibco BRL Cat # 25300-020)and incubate
• Resuspend cells in plating media and transfer into growth media.

Wash Media:

[0618] 

• HBSS Low Glucose Without Phenol Red (Gibco BRL Cat # 14175-095), 1% Ab-Am Plating Media:
• D-MEM Low Glucose Without Phenol Red (Gibco BRL Cat # 11054-020), 1 % Ab-Am D-MEM

Stripped FBS (Hyclone Cat# SH30068.03 Lot # AHM9371)
Ab-Am

Transfection / Treatment Media:

[0619] 

• D-MEM Low Glucose Without Phenol Red only

T-152 cm² culture flask:

[0620] 

• Use Coming Coastar T-152 cm² culture flask (Cat # 430825) to grow the cells

Flat well Plates:

[0621] 

• Use well plate to plate cells
• Use Deep well plate sterile to make up treatment media.

Luciferase Assay Reagent:

[0622] 

• Use Steady-Glo Luciferase Reagent from Promega (Cat # E2550) Consists of:
  a. E2533 Assay Substrate, lyopholized product and

  b. E2543 Assay Buffer.
• Thaw at room temperature
• Store

DAY 1: Cell Plating:

[0623] Cell Harvesting
Aspirate media from culture flask, rinse cells with HBSS and aspirate.
Add trypsin and incubate.
When cells appear detached, resuspend cells in growth media.
Transfer into a new flask with fresh growth media for passaging the cells.
Plate well plates and two extra plates

B. Cell Count

[0624] Mix the cell suspension using pipette
Use Hematocytometer to count the cells
Load cell suspension onto the hemocytometer chamber
Count cells.

Plate seeding:

[0625] Use plating media 10 % Stripped FBS in D-MEM Low Glucose, Without Phenol Red, 1% Ab-Am
Plate 14 plates @ 165 µl / well.
In sterile flask add cell suspension to plating media.
Mix .
Add cells / well.
Place the cells in the incubator.
Cells should be about 75 % confluent prior to transfection.

DAY 2: Transfection

[0626] Step 1: DNA and Media
Add plain DMEM media to tubes for mixing the DNA
Add the Reporter gene pFR-LUC
Add the Gal4-RXR-DEF and VP16-VDR-LBD

Step 2: FuGENE and Media

[0627] Prepare plain DMEM media in a ubes for mixing FuGENE
Add FuGENE 6 Transfection Reagent
Incubate

Step 3: FuGENE, DNA and Media Complex

[0628] Add FuGENE Media complex from step 2 to DNA Media complex from step1
Incubate

Step 4: FuGENE, DNA and Media Complex to-well plate

[0629] Add FuGENE-DNA-Media complex from step 3 to each plate
Incubate.

DAY 3: Dosing

Treatment preparation

[0630] Allow for transfection time
Make a stock solution of the compounds in DMSO
Vortex until all the compounds has been dissolved.
Further dilute in D-MEM (Low Glucose - With out Phenol Red)
Add compounds in quadruplicate to give final volume
Incubate.

Day 4: Luciferase Assay

[0631] Read the plates after drug treatment
Remove part of media from all the wells and leave remainder
Add Steady-Glo Luciferase Reagent mixture / wells
Incubate
Count each well using a Luminescence counter, Top Count NXT by Packard Set a delay between plates to reduce the background.

(2) Materials and Method for The Caco-2 Cell Assay:

[0632] Caco-2 cells, grown in phenol red free, DMEM (Invitrogen, Carlsbad, CA) containing 10 % charcoal-stripped FCS (Hyclone, Logan, UT), were transfected with Fugene 6 reagent (Roche Diagnostics, Indianapolis, IN). Cells (5000/well) were plated 18 h before transfection in a 96 well plate. The Cells were transfected with Ga14-responsive reporter pFRLuc (150 ng, Stratagene, La Jolla CA) and the receptor expression vector pGa14-VDR-LBD (10 ng), along with Fugene 6 reagent (0.2 □1/well). The DNA-Fugene complex was formed by incubating the mixture for 30 min at room temperature. The cells were transfected in triplicate for 5 h, and treated with various concentrations of VDR ligands (form 0.01 nM to 10,000 nM concentration range) 18h post-transfection. The luciferase activity was quantified using Steady-Glo reagent kit (Promega, Madison, WI) as per manufacturer's specifications.

(3) Materials and Method for The OCN Promoter Assay:

[0633] The activation of osteocalcin by VDR ligands was evaluated in a rat osteoblast-like cell line RG-15 (ROS 17/2.8) stably expressing rat osteocalcin promoter fused with luciferase reporter gene. The stable cell lines were established as reported before (Activation of Osteocalcin Transcription involves interaction of protein kinase A- and Protein kinase C-dependent pathways. Boguslawski, G., Hale, L. V., Yu, X.-P., Miles, R. R., Onyia, J. E., Santerre R. F., Chandrasekhar, S. J Biol. Chem. 275, 999-1006, 2000). Confluent RG-15 cells maintained in DMEM/F-12 medium (3:1) containing 5% FBS, 300 □g/ml G418 and at 37°C under 5% CO₂/95% air atmosphere were trypsinized (0.25% trypsin) and plated into white opaque 96-well cell culture plates (25000 cells/well). After 24 hr, cells (in DMEM/F-12 medium + 2% FBS) were treated
with various concentrations of compounds, dissolved in DMSO. The final DMSO concentration remained at 0.01% (v/v). After 48 hr treatment, the
medium was removed, cells were lysed with 50 □l of lysis buffer (From Luciferase reporter assay system, Roche Diagnostics, Indianapolis, IN) and assayed for luciferase activity using the Luciferase Reporter Gene Assay kit from Boehringer Mannheim as per manufacturer's specifications.

(4) Materials and Method for The Mouse Hypercalcemia Assay:

[0634] Weanling, virus -antibody-free, five to six weeks old female DBF mice (Harlan, Indianapolis, IN) are used for all the studies. Animals are allowed to acclimate to local vivarium conditions for 2 days. Mice are maintained on a 12 hr light/dark cycle at 22°C with ad lib access to food (TD 5001 with 1.2% Ca and 0.9%P, Teklad, Madison, WI) and water. The animals then are divided into groups with 4-5 mice per group. Different doses of test compounds prepared in 10% Ethanol and 90% sesame oil are administered to mice orally via gavage for 6 days. 1α-25(OH)₂D₃ 0.5µg/kg/d was also given to one group of mice as the positive control. Serum ionized calcium is evaluated at 6 hours after the last dosing under isoflurane anesthesia by Ciba-Corning Ca++/PH Analyzer, (Model 634, Chiron Diagnostics Corp., East Walpole, MA). Raw data of group differences is assessed by analysis of variance (ANOVA) using Fisher's protected least significant difference (PLSD) where the significance level was P< 0.05.

(5) The Keratinocyte Proliferation Assay:

[0635] KERtr cells (Human skin keratinocyte transformed with a retrovirus vector, obtained from ATCC) were plated in 96-well flat-bottomed plates (3000 cells/well) in 100 □l keratinocyte serum free medium supplemented with bovine pituitary extract in the absence of EGF (Life Technologies, Rockville, MD) and incubated at 37°C for two days. The cells were treated with various concentrations of VDR ligands (ten-fold serial dilution from 10,000 nM to 0.1 nM in triplicate), dissolved in 100 □l keratinocyte serum free medium supplemented with bovine pituitary extract in the absence of EGF and incubated at 37°C for 72hr. BrdU (5-bromo-2'-deoxyuridine) incorporation was analyzed as a measure of DNA replication (Cell proliferation ELISA kit, Roche Diagnostics, Indianapolis, IN) and absorbance was measured at 405 nm. Potency values (IC₅₀) values were determined as the concentration (nM) of compound that elicited a half-maximal response.

(6) Materials and Method for human IL-10 Induction Assay:

Isolation of peripheral blood mononuclear cells (PBMCs):

[0636] 

A. Collect 50 ml of human blood and dilute with media, RPMI-1640.

B. Prepare sterile tubes with ficol.

C. Add diluted blood to tubes.

D. Centrifuge.

E. Discard the top layer and collect the cells from middle layer.

F. Divide all cells into four tubes and add media.

G. Centrifuge.

H. Aspirate off media and resuspend.

I. Collect all cells

J. Centrifuge, at 1200 rpm for 10 minutes.

K. Resuspend in RPMI-1640 with 2% FBS and count cells Stimulation of PBMC:

L. Prepare TPA in DMSO.

M. Dissolve PHA in water.

N. Plate TPA/PHA treated PBMCs in well plates.

O. Incubate.

Treatment:

[0637] 

P. Prepare all compound dilutions in plain RPMI- 1640 media.

Q. Add diluted compound.

R. Incubate.

Sample Collection and assay:

[0638] 

S. Remove all the cells by centrifugation and assay the supernatant for IL-10 by immunoassay.

1) T. Perform IL-10 assay using anti-human IL-10 antibody coated beads, as described by the manufacturer (Linco Research Inc., St. Charles, MO).

Claims

1. A compound represented by any one of formula (X1) thru (X188) a pharmaceutically acceptable salt or solvate thereof:



























































































































































































































or

2. A compound selected from the group consisting of compounds represented by the formula:











and

or a pharmaceutically suitable salt or solvate thereof.

3. A compound selected from the group consisting of compounds represented by the formula:











or

or a pharmaceutically suitable salt or solvate thereof.

4. A compound according to Claim 1 of the formula:

or a pharmaceutically suitable salt thereof.

5. A compound according to Claim 1 of formula:

or a pharmaceutically suitable salt thereof.

6. A compound according to Claim 1 of the formula:

or a pharmaceutically suitable salt thereof.

7. A pharmaceutical formulation comprising a compound of any one of claims 1 - 6 together with a pharmaceutically acceptable carrier or diluent therefore.

8. A compound of any one of claims 1 to 6 for use as a medicament.

9. A compound of any one of claims 1 to 6 for use in treating a mammal to prevent or alleviate the pathological effects of abscess, acne, actinic keratosis, adhesion, alopecia. Alzheimer's disease, autoimmune induced diabetes, bone fracture healing, breast cancer. Crohn's disease, colon cancer. Type I diabetes, host-graft rejection, hypercalcemia. Type If diabetes, leukemia, multiple sclerosis, insufficient sebum secretion, osteomalacia, osteoporosis, insufficient dermal firmness, insufficient dermal hydration, myelodysplastic syndrome, psoriatic arthritis, prostate cancer, psoriasis, renal osteodystrophy, rheumatoid arthritis, scleroderma, seborrheic dermatitis, skin cancer, systemic lupus erythematosus, ulcerative colitis and wrinkles.

10. A compound according to claim 9 for use in treating psoriasis.

Ansprüche

1. Verbindung irgendeiner der folgenden Formeln (X1) bis (X188) oder ein pharmazeutisch akzeptables Salz oder Solvat hiervon



























































































































































































































oder

2. Verbindung, ausgewählt aus der Gruppe, die besteht aus Verbindungen der folgenden Formeln











und

oder einem pharmazeutisch akzeptablen Salz oder Solvat hiervon.

3. Verbindung, ausgewählt aus der Gruppe, die besteht aus Verbindungen der folgenden Formeln











oder

oder einem pharmazeutisch akzeptablen Salz oder Solvat hiervon.

4. Verbindung nach Anspruch 1 der Formel

oder ein pharmazeutisch akzeptables Salz hiervon.

5. Verbindung nach Anspruch 1 der Formel

oder ein pharmazeutisch akzeptables Salz hiervon.

6. Verbindung nach Anspruch 1 der Formel

oder ein pharmazeutisch akzeptables Salz hiervon.

7. Pharmazeutische Formulierung, umfassend eine Verbindung nach einem der Ansprüche 1 bis 6 zusammen mit einem pharmazeutisch akzeptablen Träger oder Verdünnungsmittel hierfür.

8. Verbindung nach einem der Ansprüche 1 bis 6 zur Verwendung als ein Arzneimittel.

9. Verbindung nach einem der Ansprüche 1 bis 6 zur Verwendung für die Behandlung eines Säugers zwecks Verhinderung oder Milderung der pathologischen Einflüsse von Abszessen, Akne, aktinischer Keratose, Adhäsion, Alopezie, Alzheimer-Krankheit, autoimmuninduziertem Diabetes, Knochenfrakturheilung, Brustkrebs, Crohn-Krankheit, Kolonkrebs, Diabetes Typ 1, Wirt-Graft-Abstoßung, Hypercalcämie, Diabetes Typ 2, Leukämie, multipler Sklerose, insuffizienter Sebumsekretion, Osteomalazie, Osteoporose, insuffizienter Hautfestigkeit, insuffizienter Hauthydration, myelodysplastischem Syndrom, psoriatischer Arthritis, Prostatakrebs, Psoriasis, Nierenosteodystrophie, rheumatoider Arthritis, Sklerodermie, seborrhöischer Dermatitis, Hautkrebs, systemischem Lupus erythematodes, ulzerativer Kolitis und Falten.

10. Verbindung nach Anspruch 9 zur Verwendung für die Behandlung von Psoriasis.

Revendications

1. Composé représenté par l'une quelconque des formules (X1) à (X188), un sel ou solvate pharmaceutiquement acceptable de celui-ci :



























































































































































































































ou

2. Composé choisi dans le groupe constitué des composés représentés par la formule :











et

ou un sel ou solvate pharmaceutiquement acceptable de celui-ci.

3. Composé choisi dans le groupe constitué des composés représentés par la formule :











ou

ou un sel ou solvate pharmaceutiquement acceptable de celui-ci.

4. Composé selon la revendication 1 de la formule :

ou un sel pharmaceutiquement acceptable de celui-ci.

5. Composé selon la revendication 1 de formule :

ou un sel pharmaceutiquement acceptable de celui-ci.

6. Composé selon la revendication 1 de la formule :

ou un sel pharmaceutiquement acceptable de celui-ci.

7. Formulation pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 6 conjointement à un support ou diluant pharmaceutiquement acceptable pour celle-ci.

8. Composé selon l'une quelconque des revendications 1 à 6 pour une utilisation en tant que médicament.

9. Composé selon l'une quelconque des revendications 1 à 6 pour une utilisation dans le traitement d'un mammifère afin de prévenir ou soulager les effets pathologiques d'un abcès, une acné, une kératose actinique, une adhérence, une alopécie, la maladie d'Alzheimer, un diabète auto-immun, une cicatrisation de fracture osseuse, un cancer du sein, la maladie de Crohn, un cancer du côlon, un diabète de type I, un rejet de greffe par l'hôte, une hypercalcémie, un diabète de type II, une leucémie, une sclérose en plaques, une sécrétion de sébum insuffisante, une ostéomalacie, l'ostéoporose, une fermeté dermique insuffisante, une hydratation dermique insuffisante, un syndrome myélodysplasique, une arthrite psoriasique, un cancer de la prostate, un psoriasis, une ostéodystrophie rénale, une arthrite rhumatoïde, une sclérodermie, une dermatite séborrhéique, un cancer de la peau, un lupus érythémateux systémique, une colite ulcéreuse et des rides.

10. Composé selon la revendication 9, pour une utilisation dans le traitement du psoriasis.